JP2020517668A - Nilaparib manufacturing method - Google Patents

Abstract

Disclosed herein are niraparib and pharmaceutically acceptable salts thereof, as well as intermediates useful in the synthesis of niraparib and methods of preparing the salts.

Description

Cross reference

This application claims the benefit of US Provisional Application No. 62/489,387 filed April 24, 2017 and US Provisional Application No. 62/489,415 filed April 24, 2017, This is incorporated by reference in its entirety.

Nilaparib is an orally effective and potent poly(ADP-ribose) polymerase, or PARP inhibitor. Nilaparib and pharmaceutically acceptable salts thereof are described in International Publication No. WO2007/113596 and European Patent No. EP2007733B1; International Publication No. WO2008/084261 and U.S. Patent No. 8,071,623; and International Publication No. WO2009/087381. And U.S. Pat. No. 8,436,185. Methods for producing nilaparib and its pharmaceutically acceptable salts are disclosed in WO2014/088983 and WO2014/088984. Methods of treating cancer with nilaparib and its pharmaceutically acceptable salts are disclosed in US Provisional Patent Applications Nos. 62/356,461, 62/402,427, and 62/470,141. ing. The contents of each of the above references are incorporated by reference in their entirety.

PARP is a family of proteins involved in many functions of cells including DNA repair, gene expression, cell cycle regulation, intracellular trafficking and energy metabolism. PARP proteins play an important role in single-strand break repair via the base excision repair pathway. PARP inhibitors have shown activity as monotherapy against tumors with pre-existing DNA repair defects such as BRCA1 and BRCA2, and as combination therapy when administered with anticancer drugs that induce DNA damage. .. PARP inhibitors have shown activity as monotherapy against tumors with pre-existing DNA repair defects such as BRCA1 and BRCA2, and as combination therapy when administered with anticancer drugs that induce DNA damage. ..

Despite some advances in the treatment of ovarian cancer, most patients eventually relapse, and their response to subsequent additional treatment is often limited in duration. Women with germline BRCA1 or BRCA2 mutations have an increased risk of developing high-grade serous ovarian cancer (HGSOC), and the tumors in such patients are particularly susceptible to treatment with PARP inhibitors. Seem. In addition, in the published scientific literature, platinum-sensitive HGSOC patients who do not have germline BRCA1 or BRCA2 mutations may also benefit clinically from treatment with PARP inhibitors.

Disclosed herein are niraparib and pharmaceutically acceptable salts thereof, as well as intermediates useful in the synthesis of niraparib and methods of making the salts.

In one aspect, equation (1):
A compound of formula (2):
A compound of formula (3):
And a salt thereof, wherein R ₁ is H or an amine protecting group; R ₂ is H, C _1-10 alkyl, C _1-10 haloalkyl, or aryl. And each R ₃ is independently H, halogen, C _1-10 alkyl, C _1-10 haloalkyl, or aryl] is disclosed herein. In some embodiments, contacting results in the formation of water molecules.

In some embodiments, the contacting is done in the presence of acid. In some embodiments, the acid is formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, oxalic acid, lactic acid, malic acid, citric acid, benzoic acid, carbonic acid, uric acid, taurine, p-toluenesulfonic acid. , Trifluoromethanesulfonic acid, aminomethylphosphonic acid, trifluoroacetic acid (TFA), phosphonic acid, sulfuric acid, nitric acid, phosphoric acid, hydrochloric acid, ethanesulfonic acid (ESA), or any combination thereof. In some embodiments, the acid is TFA.

In some embodiments, R ₁ is an amine protecting group. In some embodiments, the amine protecting group is tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), carboxybenzyl group (Cbz), p-methoxybenzylcarbonyl (Moz), acetyl. (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2-naphthylmethyl ether (Nap), tosyl (Ts), or Trichloroethyl chloroformate (Troc). In some embodiments, the amine protecting group is a tert-butyloxycarbonyl group (Boc).

In some embodiments, R ₂ is C _1-10 alkyl. In some embodiments, R ₂ is methyl. In some embodiments, each R ₃ is H.

In some embodiments, the compound of formula (1) or salt thereof has the formula (4):
It has the structure of. In some embodiments, the compound of formula (1) has the structure of formula (4).

In another aspect, equation (5):
A compound of formula (1):
A compound of claim 1 or a salt thereof with a catalyst, wherein R ₁ is H or an amine protecting group; R ₂ is H, C _1-10 alkyl, C _1-10 haloalkyl, Or aryl; and each R ₃ is independently H, halogen, C _1-10 alkyl, C _1-10 haloalkyl, or aryl] is disclosed herein.

In some embodiments, the catalyst comprises a Lewis acid, or solvate thereof. In some embodiments, the Lewis acid has the formula MXn, where M is Cu, Zn, B, Ti, Fe, Ni, Co, Al, or Ag, where X is A halide, triflate, phosphate, fluorophosphate, or acetate, where n is 1, 2, 3, or 4. In some embodiments, M is Cu. In some embodiments, the Lewis acid is a copper salt. In some embodiments, the copper salt is copper(II) trifluoromethanesulfonate (Cu(OTf) ₂ ).

In some embodiments, the contacting is conducted in the presence of solvent. In some embodiments, the solvent is N,N-dimethylformide (DMF), t-butanol, dimethoxyethane (DME), acetonitrile, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran ( ME-THF), isopropyl alcohol, methanol, ethanol, or any combination thereof. In some embodiments, the solvent comprises THF.

In some embodiments, R ₁ is an amine protecting group. In some embodiments, the amine protecting group is tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), carboxybenzyl group (Cbz), p-methoxybenzylcarbonyl (Moz), acetyl. (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2-naphthylmethyl ether (Nap), tosyl (Ts), or Trichloroethyl chloroformate (Troc). In some embodiments, the amine protecting group is a tert-butyloxycarbonyl group (Boc).

In some embodiments, R ₂ is C _1-10 alkyl. In some embodiments, R ₂ is methyl. In some embodiments, each R ₃ is H.

In some embodiments, the compound of formula (5) or salt thereof has the formula (6):
It has the structure of. In some embodiments, the compound of formula (5) has the structure of formula (6).

In another aspect, equation (7):
A salt of the formula (5):
A compound of claim 1 or a salt thereof with a metal hydroxide, wherein R ₁ is H or an amine protecting group; R ₂ is H, C _1-10 alkyl, C _{1 -. 10} haloalkyl, or aryl; each R ₃ is independently H, halogen, C _1-10 alkyl, C _1-10 haloalkyl, or aryl; and A is a cation] Disclosed in the specification.

In some embodiments, the cation is an inorganic or organic cation. In some embodiments, the cation is a metal cation. In some embodiments, the metal cation is an alkali metal cation. In some embodiments, the alkali metal cation is a lithium cation, sodium cation, potassium cation, rubidium cation, cesium cation, or francium cation. In some embodiments, the alkali metal cation is a lithium cation.

In some embodiments, R ₁ is an amine protecting group. In some embodiments, the amine protecting group is tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), carboxybenzyl group (Cbz), p-methoxybenzylcarbonyl (Moz), acetyl. (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2-naphthylmethyl ether (Nap), tosyl (Ts), or Trichloroethyl chloroformate (Troc). In some embodiments, the amine protecting group is a tert-butyloxycarbonyl group (Boc).

In some embodiments, R ₂ is C _1-10 alkyl. In some embodiments, R ₂ is methyl. In some embodiments, each R ₃ is H.

In some embodiments, the salt of formula (7) has the formula (8):
It has the structure of.

In another aspect, equation (9):
A compound of formula (7):
And a salt thereof with a coupling reagent and ammonium hydroxide, wherein R ₁ is H or an amine protecting group; R ₂ is H, C _1-10 alkyl. , C _1-10 haloalkyl, or aryl; each R ₃ is independently H, halogen, C _1-10 alkyl, C _1-10 haloalkyl, or aryl; and A is a cation. ] Are disclosed herein.

In some embodiments, the cation is an inorganic or organic cation. In some embodiments, the cation is a metal cation. In some embodiments, the metal cation is an alkali metal cation. In some embodiments, the alkali metal cation is a lithium cation, sodium cation, potassium cation, rubidium cation, cesium cation, or francium cation. In some embodiments, the alkali metal cation is a lithium cation.

In some embodiments, the coupling reagent is carbonyldiimidazole (CDI), N,N′-dicyclohexylcarbodiimide (DCC), 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazine-4( 3H)-one (DEPBT), N,N'-diisopropylcarbodiimide, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophos Fert (HATU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 1-hydroxy-7-azabenzotriazole (HOAt) , Hydroxybenzotriazole (HOBt), 7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) Is. In some embodiments, the coupling reagent is CDI.

In some embodiments, the contacting is conducted in the presence of solvent. In some embodiments, the solvent is N,N-dimethylformide (DMF), t-butanol, dimethoxyethane (DME), acetonitrile, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran ( ME-THF), isopropyl alcohol, methanol, ethanol, or any combination thereof. In some embodiments, the solvent comprises DMF.

In some embodiments, the contacting is done in the presence of acid. In some embodiments, the acid is formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, oxalic acid, lactic acid, malic acid, citric acid, benzoic acid, carbonic acid, uric acid, taurine, p-toluenesulfonic acid. , Trifluoromethanesulfonic acid, aminomethylphosphonic acid, trifluoroacetic acid (TFA), phosphonic acid, sulfuric acid, nitric acid, phosphoric acid, hydrochloric acid, ethanesulfonic acid (ESA), or any combination thereof. In some embodiments, the acid is trifluoroacetic acid (TFA).

In some embodiments, R ₁ is an amine protecting group. In some embodiments, the amine protecting group is tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), carboxybenzyl group (Cbz), p-methoxybenzylcarbonyl (Moz), acetyl. (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2-naphthylmethyl ether (Nap), tosyl (Ts), or Trichloroethyl chloroformate (Troc). In some embodiments, the amine protecting group is a tert-butyloxycarbonyl group (Boc).

In some embodiments, R ₂ is C _1-10 alkyl. In some embodiments, R ₂ is methyl. In some embodiments, each R ₃ is H.

In some embodiments, the compound of formula (9) or salt thereof has the formula (10):
It has the structure of. In some embodiments, the compound of formula (9) has the structure of formula (10).

In another aspect, equation (11):
A salt of the formula (9):
Or a salt thereof with para-toluenesulfonic acid monohydrate (pTSA.H ₂ O), wherein R ₁ is H or an amine protecting group; R ₂ is , H, C _1-10 alkyl, C _1-10 haloalkyl, or aryl; and each R ₃ is independently H, halogen, C _1-10 alkyl, C _1-10 haloalkyl, or aryl. ] Are disclosed herein.

In some embodiments, the contacting is done in the presence of acid. In some embodiments, the acid is formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, oxalic acid, lactic acid, malic acid, citric acid, benzoic acid, carbonic acid, uric acid, taurine, p-toluenesulfonic acid. , Trifluoromethanesulfonic acid, aminomethylphosphonic acid, trifluoroacetic acid (TFA), phosphonic acid, sulfuric acid, nitric acid, phosphoric acid, hydrochloric acid, ethanesulfonic acid (ESA), or any combination thereof. In some embodiments, the acid is trifluoroacetic acid (TFA).

In some embodiments, the contacting is conducted in the presence of solvent. In some embodiments, the solvent is N,N-dimethylformide (DMF), t-butanol, dimethoxyethane (DME), acetonitrile, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran ( ME-THF), isopropyl alcohol, methanol, ethanol, or any combination thereof. In some embodiments, the solvent comprises THF.

In some embodiments, R ₁ is an amine protecting group. In some embodiments, the amine protecting group is tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), carboxybenzyl group (Cbz), p-methoxybenzylcarbonyl (Moz), acetyl. (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2-naphthylmethyl ether (Nap), tosyl (Ts), or Trichloroethyl chloroformate (Troc). In some embodiments, the amine protecting group is a tert-butyloxycarbonyl group (Boc).

In some embodiments, R ₂ is C _1-10 alkyl. In some embodiments, R ₂ is methyl. In some embodiments, each R ₃ is H.

In some embodiments, the salt of formula (11) has the formula (12):
It has the structure of.

In another aspect, equation (12):
A process for producing an enantiomerically enriched tosylate (S)-nilaparib monohydrate comprising: (S)-niraparib monohydrate tosylate (R)-niraparib monohydrate Contacting the mixture with water and a first organic solvent; separating the tosylate (S)-nilaparib monohydrate from the mixture by filtration to obtain the enantiomerically enriched tosylate (S)-nilaparib monohydrate. Forming; and contacting the enantiomerically enriched tosylate (S)-nilaparib monohydrate with a second organic solvent, water, or any combination thereof, to form the enantiomerically enriched tosylate (S)-nilaparib monohydrate. Disclosed herein is a method comprising forming a crystalline form of a hydrate.

In some embodiments, the method further comprises wet milling the crystalline form of the enantiomerically enriched (S)-nilaparib monohydrate tosylate. In some embodiments, the method further comprises annealing the enantiomerically enriched (S)-nilaparib monohydrate with one or more temperature cycles.

In some embodiments, the first organic solvent comprises acetonitrile. In some embodiments, a water:first organic solvent ratio (v/v) of about 200:1 to about 1:200 is used for the contact. In some embodiments, the water:first organic solvent ratio (v/v) is about 200:1 to about 1:200, such as about 200:1 to about 100:1, about 200:1. To about 10:1, about 200:1 to about 5:1, about 200:1 to about 2:1, about 200:1 to about 1:1, about 200:1 to about 1:2, about 200:1. To about 1:5, about 200:1 to about 1:10, about 200:1 to about 1:100, about 100:1 to about 10:1, about 100:1 to about 5:1, about 100:1. To about 2:1, about 100:1 to about 1:1, about 100:1 to about 1:2, about 100:1 to about 1:5, about 100:1 to about 1:10, about 100:1. To about 1:100, about 100:1 to about 1:200, about 10:1 to about 5:1, about 10:1 to about 2:1, about 10:1 to about 1:1, about 10:1. To about 1:2, about 10:1 to about 1:5, about 10:1 to about 1:10, about 10:1 to about 1:100, about 10:1 to about 1:200, about 5:1. To about 2:1, about 5:1 to about 1:1, about 5:1 to about 1:2, about 5:1 to about 1:5, about 5:1 to about 1:10, about 5:1. To about 1:100, about 5:1 to about 1:200, about 2:1 to about 1:1, about 2:1 to about 1:2, about 2:1 to about 1:5, about 2:1. To about 1:10, about 2:1 to about 1:100, about 2:1 to about 1:200, about 1:1 to about 1:2, about 1:1 to about 1:5, about 1:1. To about 1:10, about 1:1 to about 1:100, about 1:1 to about 1:200, about 1:2 to about 1:5, about 1:2 to about 1:10, about 1:2. To about 1:100, about 1:2 to about 1:200, about 1:5 to about 1:10, about 1:5 to about 1:100, about 1:5 to about 1:200, about 1:10. To about 1:100, about 1:10 to about 1:200, or about 1:100 to about 1:200. In some embodiments, the water:first organic solvent ratio (v/v) is about 5:1 to about 1:5.

In some embodiments, the water:first organic solvent ratio (v/v) is about 1:0.005, about 1:0.01, about 1:0.02, about 1:0.03, About 1:0.04, about 1:0.05, about 1:0.1, about 1:0.2, about 1:0.3, about 1:0.4, about 1:0.5, about 1:0.6, about 1:0.7, about 1:0.8, about 1:0.9, about 1:1, about 1:1.5, about 1:2, about 1:2.5 , About 1:3, about 1:3.5, about 1:4, about 1:4.5, about 1:5, about 1:5.5, about 1:6, about 1:6.5, about 1:7, about 1:7.5, about 1:8, about 1:8.5, about 1:9, about 1:9.5, about 1:10, about 1:20, about 1:30, It is about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:150, or about 1:200.

In some embodiments, the enantiomerically enriched (S)-nilaparib monohydrate is present in the filtrate portion after filtration (eg, passes through the filter). In some embodiments, at least about 1% of enantiomerically enriched (S)-nilaparib monohydrate is present in the filtrate portion after filtration. For example, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10. %, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%. %, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%. %, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% enantiomerically enriched tosylic acid (S)-nilaparib monohydrate is present in the filtrate portion after filtration. Exists.

In some embodiments, the second organic solvent comprises DMSO. In some embodiments, the method comprises contacting the enantiomerically enriched tosyl acid (S)-nilaparib monohydrate with dimethyl sulfoxide (DMSO) and water. In some embodiments, a water:second organic solvent ratio (v/v) of about 200:1 to about 1:200 is used for contacting. In some embodiments, the water:second organic solvent ratio (v/v) is about 200:1 to about 1:200, such as about 200:1 to about 100:1, about 200:1 to about. 10:1, about 200:1 to about 5:1, about 200:1 to about 2:1, about 200:1 to about 1:1, about 200:1 to about 1:2, about 200:1 to about 1:5, about 200:1 to about 1:10, about 200:1 to about 1:100, about 100:1 to about 10:1, about 100:1 to about 5:1, about 100:1 to about. 2:1, about 100:1 to about 1:1, about 100:1 to about 1:2, about 100:1 to about 1:5, about 100:1 to about 1:10, about 100:1 to about 1:100, about 100:1 to about 1:200, about 10:1 to about 5:1, about 10:1 to about 2:1, about 10:1 to about 1:1, about 10:1 to about. 1:2, about 10:1 to about 1:5, about 10:1 to about 1:10, about 10:1 to about 1:100, about 10:1 to about 1:200, about 5:1 to about. 2:1, about 5:1 to about 1:1, about 5:1 to about 1:2, about 5:1 to about 1:5, about 5:1 to about 1:10, about 5:1 to about 1:100, about 5:1 to about 1:200, about 2:1 to about 1:1, about 2:1 to about 1:2, about 2:1 to about 1:5, about 2:1 to about. 1:10, about 2:1 to about 1:100, about 2:1 to about 1:200, about 1:1 to about 1:2, about 1:1 to about 1:5, about 1:1 to about. 1:10, about 1:1 to about 1:100, about 1:1 to about 1:200, about 1:2 to about 1:5, about 1:2 to about 1:10, about 1:2 to about. 1:100, about 1:2 to about 1:200, about 1:5 to about 1:10, about 1:5 to about 1:100, about 1:5 to about 1:200, about 1:10 to about. 1:100, about 1:10 to about 1:200, or about 1:100 to about 1:200. In some embodiments, the water:second organic solvent ratio (v/v) is about 5:1 to about 1:5.

In some embodiments, the water:second organic solvent ratio (v/v) is about 1:0.005, about 1:0.01, about 1:0.02, about 1:0.03, About 1:0.04, about 1:0.05, about 1:0.1, about 1:0.2, about 1:0.3, about 1:0.4, about 1:0.5, about 1:0.6, about 1:0.7, about 1:0.8, about 1:0.9, about 1:1, about 1:1.5, about 1:2, about 1:2.5 , About 1:3, about 1:3.5, about 1:4, about 1:4.5, about 1:5, about 1:5.5, about 1:6, about 1:6.5, about 1:7, about 1:7.5, about 1:8, about 1:8.5, about 1:9, about 1:9.5, about 1:10, about 1:20, about 1:30, It is about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:150, or about 1:200.

In some embodiments, (S)-nilaparib monohydrate and (R)-nilaparib monohydrate tosylate (R)-niraparib monohydrate are at least 50%, at least 60%, at least 70%, at least 80%, at least 85. %, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.1%, at least 99%. Enantiomeric excess of .2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or at least 99.9%. Have a rate.

In another aspect, equation (12):
Of the enantiomerically enriched tosylate (S)-nilaparib monohydrate of formula (13):
A salt of formula (14) with sodium hydroxide and toluene.
Forming a compound of formula (15):
By contacting a compound of formula (16) with sodium azide, ethyl acetate and DMSO:
A compound of formula (14) is contacted with a compound of formula (16) and TFA to form a compound of formula (4):
A compound of formula (4) is contacted with copper(II) trifluoromethanesulfonate (Cu(OTf) ₂ ), THF and toluene to form a compound of formula (6):
A compound of formula (6) is contacted with lithium hydroxide and ethanol to form a compound of formula (8):
A salt of formula (8) is contacted with CDI, TFA, N,N-dimethylformide (DMF), and ammonium hydroxide to form a salt of formula (10):
A compound of formula (10) is contacted with p-toluenesulfonic acid monohydrate (pTsOH.H ₂ O) and THF to form a compound of formula (12):
Forming (S)-nilaparib monohydrate of formula (12); contacting the tosylate (S)-nilaparib monohydrate of formula (12) with acetonitrile and water to form a mixture; Separating tosylate (S)-nilaparib monohydrate from the mixture to form an enantiomerically enriched tosylate (S)-nilaparib monohydrate; and enantiomerically enriched tosylate (S)-nilaparib monohydrate Disclosed herein is a method comprising contacting a hydrate with DMSO and water to form a crystalline form of enantiomerically enriched (S)-nilaparib monohydrate. In some embodiments, the method further comprises wet milling the crystalline form of the enantiomerically enriched (S)-nilaparib monohydrate tosylate. In some embodiments, the method further comprises annealing the enantiomerically enriched (S)-nilaparib monohydrate with one or more temperature cycles.

In another aspect, equation (7):
Wherein R ₁ is H or an amine protecting group; each R ₃ is independently H, halogen, C _1-10 alkyl, C _1-10 haloalkyl, or aryl; and A Are cations] are disclosed herein. In some embodiments, the cation is an inorganic or organic cation. In some embodiments, the cation is a metal cation. In some embodiments, the metal cation is an alkali metal cation. In some embodiments, the alkali metal cation is a lithium cation. In some embodiments, R ₁ is an amine protecting group. In some embodiments, the amine protecting group is tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), carboxybenzyl group (Cbz), p-methoxybenzylcarbonyl (Moz), acetyl. (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2-naphthylmethyl ether (Nap), tosyl (Ts), or Trichloroethyl chloroformate (Troc). In some embodiments, the amine protecting group is a tert-butyloxycarbonyl group (Boc). In some embodiments, each R ₃ is H. In some embodiments, the salt of formula (7) has the formula (8):
It has the structure of.

In another aspect, equation (17):
A compound of formula (18):
Compound or method wherein, R ₄ is a leaving group, comprising contacting a salt thereof n- butyl lithium and triisopropyl borate (B (Oi-Pr) 3 ) is hereby of Disclosed in the book. In some embodiments, the method further comprises a hydrolysis reaction. In some embodiments, the method comprises formula (19):
Contacting a compound of formula (18) or a salt thereof with benzoyl chloride and an organic compound to form a compound of formula (18) or salt thereof, wherein R ₄ is a leaving group. In some embodiments, the organic compound is trimethylamine (TEA) or trimethylamine (TMA). In some embodiments, the leaving group is, for example, dinitrogen, dialkyl ether, perfluoroalkyl sulfonate (eg, triflate), tosylate, mesylate, iodide, bromide, water, alcohol, chloride. , Nitrates, phosphates, esters, thioethers, amines, ammonia, fluorides, carboxylates, phenol salts, hydroxides, alkoxides or amides. In some embodiments, R ₄ is Br. In some embodiments, the contacting is conducted in the presence of solvent. In some embodiments, the solvent is N,N-dimethylformide (DMF), t-butanol, dimethoxyethane (DME), acetonitrile, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran ( ME-THF), isopropyl alcohol, methanol, ethanol, or any combination thereof. In some embodiments, the solvent comprises THF.

In another aspect, equation (20):
A method for producing the compound or a salt thereof according to formula (17):
A compound of formula (21):
Disclosed herein is a method comprising contacting the salt of claim 1 with a catalyst in the presence of a catalyst. In some embodiments, contacting the compound of formula (17) or a salt thereof comprises contacting a compound of formula (22):
Further comprising contacting the salt of. Further, in the present specification, the formula (26):
A method for producing the compound or a salt thereof according to formula (17):
A compound of formula (22):
Disclosed is a method comprising contacting the salt of claim 1 with a salt in the presence of a catalyst.

In some embodiments, the salt of formula (21) and the salt of formula (22) are about 200:1 to about 1:200, such as about 200:1 to about 100:1, about 200:1 to about 200:1. 10:1, about 200:1 to about 5:1, about 200:1 to about 2:1, about 200:1 to about 1:1, about 200:1 to about 1:2, about 200:1 to about 1:5, about 200:1 to about 1:10, about 200:1 to about 1:100, about 100:1 to about 10:1, about 100:1 to about 5:1, about 100:1 to about. 2:1, about 100:1 to about 1:1, about 100:1 to about 1:2, about 100:1 to about 1:5, about 100:1 to about 1:10, about 100:1 to about 1:100, about 100:1 to about 1:200, about 10:1 to about 5:1, about 10:1 to about 2:1, about 10:1 to about 1:1, about 10:1 to about. 1:2, about 10:1 to about 1:5, about 10:1 to about 1:10, about 10:1 to about 1:100, about 10:1 to about 1:200, about 5:1 to about. 2:1, about 5:1 to about 1:1, about 5:1 to about 1:2, about 5:1 to about 1:5, about 5:1 to about 1:10, about 5:1 to about 1:100, about 5:1 to about 1:200, about 2:1 to about 1:1, about 2:1 to about 1:2, about 2:1 to about 1:5, about 2:1 to about. 1:10, about 2:1 to about 1:100, about 2:1 to about 1:200, about 1:1 to about 1:2, about 1:1 to about 1:5, about 1:1 to about. 1:10, about 1:1 to about 1:100, about 1:1 to about 1:200, about 1:2 to about 1:5, about 1:2 to about 1:10, about 1:2 to about. 1:100, about 1:2 to about 1:200, about 1:5 to about 1:10, about 1:5 to about 1:100, about 1:5 to about 1:200, about 1:10 to about. It has a ratio (w/w) of 1:100, about 1:10 to about 1:200, or about 1:100 to about 1:200. In some embodiments, the salt of formula (21) and the salt of formula (22) have a ratio (w/w) of about 10:1 to about 1:1.

In some embodiments, the salt of formula (21) and the salt of formula (22) are about 1:0.005, about 1:0.01, about 1:0.02, about 1:0.03, About 1:0.04, about 1:0.05, about 1:0.1, about 1:0.2, about 1:0.3, about 1:0.4, about 1:0.5, about 1:0.6, about 1:0.7, about 1:0.8, about 1:0.9, about 1:1, about 1:1.5, about 1:2, about 1:2.5 , About 1:3, about 1:3.5, about 1:4, about 1:4.5, about 1:5, about 1:5.5, about 1:6, about 1:6.5, about 1:7, about 1:7.5, about 1:8, about 1:8.5, about 1:9, about 1:9.5, about 1:10, about 1:20, about 1:30, Ratios (w/ about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:150, or about 1:200. w). In some embodiments, the salt of formula (21) and the salt of formula (22) have a ratio (w/w) of about 7:1. In some embodiments, the salt of formula (21) and the salt of formula (22) have a ratio (w/w) of about 9:1.

In some embodiments, the contacting is done in the presence of a ligand. In some embodiments, the ligand comprises a phosphine ligand. In some embodiments, the phosphine ligand comprises DavePhos, XantPhos, JohnPhos, SPhos, XPhos, tBuXPhos, APhos, CyJohnPhos, or any combination thereof. In some embodiments, the phosphine ligand comprises XPhos. In some embodiments, the phosphine ligand can be optically enriched. In some embodiments, the phosphine ligand can be optically enriched prior to use in the methods disclosed herein. In some embodiments, the phosphine ligand (eg, an optically enriched phosphine ligand) is at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%. %, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.1%, at least 99.2%, It has an enantiomeric excess of at least 99.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or at least 99.9%.

In some embodiments, the catalyst comprises a metal catalyst. In some embodiments, the metal catalyst comprises a transition metal catalyst. In some embodiments, the metal catalyst is scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver, cadmium. , Hafnium, tantalum, tungsten, rhenium, osmium, iridium, platinum, gold, mercury, rutherfordium, dobnium, seaborgium, bolium, hassium, mitnerium, unununilium, unununium, or ununbium. In some embodiments, the metal catalyst comprises palladium. In some embodiments, the metal catalyst comprises palladium(II) acetate.

In some embodiments, the contacting is performed in the presence of base. In some embodiments, the base comprises an alkali salt. In some embodiments, the alkali _{salt, Cs 2 CO 3, CsHCO 3} K 3 PO 4, K 2 HPO 4, KH 2 PO 4, K 2 CO 3, KHCO 3, NaHCO 3, Na 2 CO 3 or, It comprises any combination thereof.

In some embodiments, the contacting is conducted in the presence of solvent. In some embodiments, the solvent is N,N-dimethylformide (DMF), t-butanol, dimethoxyethane (DME), acetonitrile, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran ( ME-THF), isopropyl alcohol, methanol, ethanol, or any combination thereof. In some embodiments, the solvent comprises THF. In some embodiments, the method further comprises contacting the compound of formula (20) or salt thereof with acetonitrile.

In another aspect, equation (23):
A method for producing the compound or a salt thereof according to formula (17):
Of the compound or its salt
Disclosed herein is a method comprising contacting with, wherein each R ₅ is independently H or C _1-3 alkyl. In some embodiments, each R ₅ is independently C _1-3 alkyl. In some embodiments, each R ₅ is methyl. In some embodiments, the compound of formula (23) or salt thereof has the formula (24):
It has the structure of.

In some embodiments, the contacting is conducted in the presence of solvent. In some embodiments, the solvent is N,N-dimethylformide (DMF), t-butanol, dimethoxyethane (DME), acetonitrile, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran ( ME-THF), isopropyl alcohol, methanol, ethanol, or any combination thereof. In some embodiments, the solvent comprises THF.

In another aspect, equation (20):
A compound of formula (23):
A compound of formula (21):
Disclosed herein is a method comprising contacting the salt of claim 1 with a catalyst in the presence of a catalyst. Further, in the present specification, the formula (26):
A compound of formula (23):
A compound of formula (22):
Disclosed is a method comprising contacting with a salt of

In some embodiments, the salt of formula (21) and the salt of formula (22) are about 200:1 to about 1:200, such as about 200:1 to about 100:1, about 200:1 to about 200:1. 10:1, about 200:1 to about 5:1, about 200:1 to about 2:1, about 200:1 to about 1:1, about 200:1 to about 1:2, about 200:1 to about 1:5, about 200:1 to about 1:10, about 200:1 to about 1:100, about 100:1 to about 10:1, about 100:1 to about 5:1, about 100:1 to about. 2:1, about 100:1 to about 1:1, about 100:1 to about 1:2, about 100:1 to about 1:5, about 100:1 to about 1:10, about 100:1 to about 1:100, about 100:1 to about 1:200, about 10:1 to about 5:1, about 10:1 to about 2:1, about 10:1 to about 1:1, about 10:1 to about. 1:2, about 10:1 to about 1:5, about 10:1 to about 1:10, about 10:1 to about 1:100, about 10:1 to about 1:200, about 5:1 to about. 2:1, about 5:1 to about 1:1, about 5:1 to about 1:2, about 5:1 to about 1:5, about 5:1 to about 1:10, about 5:1 to about 1:100, about 5:1 to about 1:200, about 2:1 to about 1:1, about 2:1 to about 1:2, about 2:1 to about 1:5, about 2:1 to about. 1:10, about 2:1 to about 1:100, about 2:1 to about 1:200, about 1:1 to about 1:2, about 1:1 to about 1:5, about 1:1 to about. 1:10, about 1:1 to about 1:100, about 1:1 to about 1:200, about 1:2 to about 1:5, about 1:2 to about 1:10, about 1:2 to about. 1:100, about 1:2 to about 1:200, about 1:5 to about 1:10, about 1:5 to about 1:100, about 1:5 to about 1:200, about 1:10 to about. It has a ratio (w/w) of 1:100, about 1:10 to about 1:200, or about 1:100 to about 1:200. In some embodiments, the salt of formula (21) and the salt of formula (22) have a ratio (w/w) of about 10:1 to about 1:1.

In some embodiments, the salt of formula (21) and the salt of formula (22) are about 1:0.005, about 1:0.01, about 1:0.02, about 1:0.03, About 1:0.04, about 1:0.05, about 1:0.1, about 1:0.2, about 1:0.3, about 1:0.4, about 1:0.5, about 1:0.6, about 1:0.7, about 1:0.8, about 1:0.9, about 1:1, about 1:1.5, about 1:2, about 1:2.5 , About 1:3, about 1:3.5, about 1:4, about 1:4.5, about 1:5, about 1:5.5, about 1:6, about 1:6.5, about 1:7, about 1:7.5, about 1:8, about 1:8.5, about 1:9, about 1:9.5, about 1:10, about 1:20, about 1:30, Ratios (w/ about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:150, or about 1:200. w). In some embodiments, the salt of formula (21) and the salt of formula (22) have a ratio (w/w) of about 7:1. In some embodiments, the salt of formula (21) and the salt of formula (22) have a ratio (w/w) of about 9:1.

In some embodiments, the contacting is done in the presence of a ligand. In some embodiments, the ligand comprises a phosphine ligand. In some embodiments, the phosphine ligand comprises DavePhos, XantPhos, JohnPhos, SPhos, XPhos, tBuXPhos, APhos, CyJohnPhos, or any combination thereof. In some embodiments, the phosphine ligand comprises XPhos.

In some embodiments, the catalyst comprises a metal catalyst. In some embodiments, the metal catalyst comprises a transition metal catalyst. In some embodiments, the metal catalyst is scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver, cadmium. , Hafnium, tantalum, tungsten, rhenium, osmium, iridium, platinum, gold, mercury, rutherfordium, dobnium, seaborgium, bolium, hassium, mitnerium, unununilium, unununium, or ununbium. In some embodiments, the metal catalyst comprises palladium. In some embodiments, the metal catalyst comprises palladium(II) acetate.

In some embodiments, the contacting is performed in the presence of base. In some embodiments, the base comprises an alkali salt. In some embodiments, the alkali _{salt, Cs 2 CO 3, CsHCO 3} K 3 PO 4, K 2 HPO 4, KH 2 PO 4, K 2 CO 3, KHCO 3, NaHCO 3, Na 2 CO 3 or, It comprises any combination thereof.

In some embodiments, the contacting is conducted in the presence of solvent. In some embodiments, the solvent is N,N-dimethylformide (DMF), t-butanol, dimethoxyethane (DME), acetonitrile, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran ( ME-THF), isopropyl alcohol, methanol, ethanol, or any combination thereof. In some embodiments, the solvent comprises THF. In some embodiments, the method further comprises contacting the compound of formula (20) or salt thereof with acetonitrile.

In another aspect, equation (25):
A compound of formula (20):
Disclosed herein is a method comprising contacting a compound of claim 1 or a salt thereof with a ligand. In some embodiments, the method comprises formula (26):
Further comprising contacting the compound of claim 1 or a salt thereof with a ligand.

In some embodiments, the ligand comprises a chiral ligand. In some embodiments, the chiral ligand comprises a Josiphos ligand. In some embodiments, the Josiphos ligand comprises Josiphos SL-J505-2, Josiphos SL-J013, Josiphos SL-J212, Josiphos SL-J011, Josiphos SL-N012, or any combination thereof. In some embodiments, the contacting is done in the presence of a metal salt. In some embodiments, the metal salt comprises rhodium. In some embodiments, the metal salt comprises rhodium(I). In some embodiments, the metal salt comprises bis(norbornenadine)rhodium(I) tetrafluoroborate (Rh(nbd) ₂ BF ₄ ). In some embodiments, the ligand can be optically enriched. In some embodiments, the ligand can be optically enriched prior to use in the methods disclosed herein. In some embodiments, the ligand (eg, optically enriched ligand) is at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, At least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.1%, at least 99.2%, at least 99. It has an enantiomeric excess of 0.3%, at least 99.4%, at least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or at least 99.9%.

In some embodiments, the contacting is conducted in the presence of solvent. In some embodiments, the solvent is N,N-dimethylformide (DMF), t-butanol, dimethoxyethane (DME), acetonitrile, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran ( ME-THF), isopropyl alcohol, methanol, ethanol, or any combination thereof. In some embodiments, the solvent comprises DCM.

In another aspect, equation (14):
A compound of formula (25):
Disclosed herein is a method comprising contacting a compound of claim 1 or a salt thereof with a base. In some embodiments, the base comprises alkali hydroxide. In some embodiments, the alkali hydroxide is lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH), rubidium hydroxide (RbOH), or cesium hydroxide (CsOH). In some embodiments, the alkali hydroxide comprises sodium hydroxide.

In some embodiments, the contacting is conducted in the presence of solvent. In some embodiments, the solvent is N,N-dimethylformide (DMF), t-butanol, dimethoxyethane (DME), acetonitrile, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran ( ME-THF), isopropyl alcohol, methanol, ethanol, or any combination thereof. In some embodiments, the solvent comprises ethanol.

In another aspect, equation (13):
A salt of the formula (14):
Disclosed herein is a method comprising contacting a compound of claim 1 or a salt thereof with an acid. In some embodiments, the acid is formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, oxalic acid, lactic acid, malic acid, citric acid, benzoic acid, carbonic acid, uric acid, taurine, p-toluenesulfonic acid. , Trifluoromethanesulfonic acid, aminomethylphosphonic acid, trifluoroacetic acid (TFA), phosphonic acid, sulfuric acid, nitric acid, phosphoric acid, hydrochloric acid, ethanesulfonic acid (ESA), or any combination thereof. In some embodiments, the acid is ESA.

In some embodiments, the contacting is conducted in the presence of solvent. In some embodiments, the solvent is N,N-dimethylformide (DMF), t-butanol, dimethoxyethane (DME), acetonitrile, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran ( ME-THF), isopropyl alcohol, methanol, ethanol, or any combination thereof. In some embodiments, the solvent comprises acetonitrile, methanol, DCM, or any combination thereof. In some embodiments, the solvent comprises acetonitrile and methanol.

In some embodiments, the solvent has a methanol:acetonitrile ratio of about 0.1% to 99% (v/v). For example, the methanol:acetonitrile ratio (v/v) is about 0.1% to 1%, about 0.1% to 5%, about 0.1 to 10%, about 0.1% to 20%, about 0. 0.5% to 1%, about 0.5% to 5%, about 0.5% to 10%, about 0.5% to 20%, about 1% to 5%, about 1% to 10%, about 1 %-20%, about 5%-10%, about 5%-20%, about 10%-20%, about 10%-30%, about 20%-30%, about 20%-40%, about 30% -40%, about 30%-50%, about 40%-50%, about 40%-60%, about 50%-60%, about 50%-70%, about 60%-70%, about 60%- 80%, about 70%-80%, about 70%-90%, about 80%-90%, about 80%-95%, about 90%-95%, about 90%-99%, or about 95%- It is 99%. In some embodiments, the methanol:acetonitrile ratio (v/v) is about 1%-50%.

In some embodiments, the solvent comprises acetonitrile and DCM. For example, the DCM:acetonitrile ratio (v/v) is about 0.1% to 1%, about 0.1% to 5%, about 0.1 to 10%, about 0.1% to 20%, about 0. 0.5% to 1%, about 0.5% to 5%, about 0.5% to 10%, about 0.5% to 20%, about 1% to 5%, about 1% to 10%, about 1 %-20%, about 5%-10%, about 5%-20%, about 10%-20%, about 10%-30%, about 20%-30%, about 20%-40%, about 30% -40%, about 30%-50%, about 40%-50%, about 40%-60%, about 50%-60%, about 50%-70%, about 60%-70%, about 60%- 80%, about 70%-80%, about 70%-90%, about 80%-90%, about 80%-95%, about 90%-95%, about 90%-99%, or about 95%- It is 99%. In some embodiments, the DCM:acetonitrile ratio (v/v) is about 1%-50%.

In some embodiments, formula (14):
Or a salt thereof and a formula (27):
Or at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%. , At least 96%, at least 97%, at least 98%, at least 99%, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%, at least 99.5%, at least 99. It has an enantiomeric excess of 6%, at least 99.7%, at least 99.8%, or at least 99.9%.

In another aspect, equation (21):
A compound of formula (28):
Of the compound of formula (29):
Disclosed herein is forming a compound of formula (29) or a salt thereof; and contacting a compound of formula (29) or salt thereof with p-toluenesulfonic anhydride. In some embodiments, the oxidation is done in the presence of an oxidizing agent. In some embodiments, the oxidation is performed in the presence of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO).

In some embodiments, the oxidizing or contacting is performed in the presence of solvent. In some embodiments, the solvent is N,N-dimethylformide (DMF), t-butanol, dimethoxyethane (DME), acetonitrile, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran ( ME-THF), isopropyl alcohol, methanol, ethanol, or any combination thereof. In some embodiments, the solvent comprises DCM.

In some embodiments, formula (28):
Oxidation of the compound or a salt thereof is carried out in the presence of sodium bicarbonate, potassium bromide, sodium sulfite, or any combination thereof. In some embodiments, contacting the compound of formula (29) or salt thereof is conducted in the presence of triethylamine (TEA), water, isopropyl alcohol, sodium azide, or any combination thereof.

In some embodiments, contacting the compound of formula (29) or salt thereof comprises reacting the compound of formula (21):
And a compound of formula (22):
Resulting in the formation of a mixture of compounds.

In another aspect, equation (30):
Or a salt thereof, wherein each R ₁ is independently H or an amine protecting group; and each R ₃ is independently H, halogen, C _1-10 alkyl, C _1-10. Are haloalkyl, or aryl] are disclosed herein.

In some embodiments, each R ₁ is independently an amine protecting group. In some embodiments, the amine protecting group is tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), carboxybenzyl group (Cbz), p-methoxybenzylcarbonyl (Moz), acetyl. (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2-naphthylmethyl ether (Nap), tosyl (Ts), or Trichloroethyl chloroformate (Troc). In some embodiments, the amine protecting group is a tert-butyloxycarbonyl group (Boc) or benzoyl (Bz). In some embodiments, each R ₃ is H.

In another aspect, equation (31) or (32):
Or a salt thereof, wherein each R ₁ is independently H or an amine protecting group; and each R ₃ is independently H, halogen, C _1-10 alkyl, C _1-10. Are haloalkyl, or aryl] are disclosed herein.

In some embodiments, each R ₁ is independently an amine protecting group. In some embodiments, the amine protecting group is tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), carboxybenzyl group (Cbz), p-methoxybenzylcarbonyl (Moz), acetyl. (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2-naphthylmethyl ether (Nap), tosyl (Ts), or Trichloroethyl chloroformate (Troc). In some embodiments, the amine protecting group is a tert-butyloxycarbonyl group (Boc) or benzoyl (Bz). In some embodiments, each R ₃ is H.

In some embodiments, the compound or salt thereof has the formula (20):
Or equation (26):
It has the structure of. In some embodiments, the compound or salt thereof has the structure of formula (20). In some embodiments, the compound or salt thereof has the structure of formula (20).

REFERENCES All publications, patents, and patent applications mentioned in this specification are hereby incorporated by reference in each individual publication, patent, or patent application specifically and individually. To the same extent as if indicated to be made.

The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention may be obtained by reference to the following detailed description and accompanying drawings that illustrate exemplary embodiments in which the principles of the invention are utilized.

FIG. 1 shows the synthesis of the compound methyl 3-formyl-2-nitrobenzoate (aldehyde A). FIG. 2 shows the synthesis of compound (S)-4-(1-(tert-butoxycarbonyl)piperidin-3-yl)benzeneaminium ethanesulfonate (aniline ESA salt). FIG. 3 shows the synthesis of the compound nilaparib tosylate monohydrate.

Detailed explanation of the invention

As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes more than one such agent, and reference to "the salt" refers to one or more salts (or salts) and to those of skill in the art. And its equivalents known in the art. When ranges are used herein for physical properties such as molecular weight or chemical properties such as chemical formulas, all and subcombinations of the ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or numerical range means that the number or numerical range referred to is an approximation within experimental variation (or within statistical experimental error), and A number or numerical range can vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprises" or "comprises" or "comprising" or "comprising") is Are not intended to exclude in certain embodiments of, for example, any composition of matter, composition, method, or method described herein. Embodiments such as a process can "consist of" or "consist essentially of" the features described.

As used in this specification and the appended claims, unless otherwise indicated, the following terms have the meanings set forth below.

The compounds disclosed herein may contain one or more asymmetric centers and thus may be defined in terms of absolute stereochemistry as (R)- or (S)- enantiomers, diastereomers, and Other stereoisomeric forms may occur. Unless otherwise stated, all stereoisomeric forms of the compounds disclosed herein are intended to be contemplated by this disclosure. Where the compounds described herein contain an alkene double bond, this disclosure is meant to include both E and Z geometric isomers (eg, cis or trans) unless otherwise indicated. Also included are all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms. The term "geometric isomer" means the E or Z geometric isomer of an alkene double bond (eg, cis or trans). The term "positional isomer" means structural isomers around a central ring, such as ortho, meta, and para isomers around a benzene ring.

"Enantiomeric excess (ee)" means the extent to which a sample contains one enantiomer in a greater amount than another. For example, a racemic mixture has an ee of 0%, whereas a single, completely pure enantiomer has an ee of 100%. In another example, a sample with 70% of one enantiomer and 30% of the other has an ee of 40% (70%-30%). For example, if there are two enantiomers and their mole or weight percentages are R and S, then ee can be calculated as ee=[(R−S)/(R+S)]*100%. For example, a racemic mixture (R=S=50%) has an ee of 0%, whereas a single completely pure enantiomer has an ee of 100%. In another example, a sample with 70% of one enantiomer and 30% of the other has an ee of 40% (70%-30%). In some embodiments, the enantiomers disclosed herein are at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.1%, at least 99.2%, at least 99.3%, at least 99.4%. , At least 99.5%, at least 99.6%, at least 99.7%, at least 99.8%, or at least 99.9%.

“Amino” means the radical —NH ₂ .

“Alkyl” means a straight or branched hydrocarbon chain radical having only 1 to 15 carbon atoms (eg, C _1-15 alkyl), containing no unsaturation, and consisting solely of carbon and hydrogen atoms. In certain embodiments, alkyl comprises 1 to 13 carbon atoms (eg, C _1-13 alkyl). In certain embodiments, alkyl comprises 1-10 carbon atoms (eg, C _1-10 alkyl). In certain embodiments, alkyl comprises 1-8 carbon atoms (eg, C _1-8 alkyl). In other embodiments, alkyl comprises 1 to 5 carbon atoms (eg, C _1-5 alkyl). In another embodiment, the alkyl comprises 1-4 carbon atoms (eg, C _1-4 alkyl). In another embodiment, the alkyl comprises 1-3 carbon atoms (eg, C _1-3 alkyl). In another embodiment, the alkyl comprises 1-2 carbon atoms (eg, C _1-2 alkyl). In other embodiments, alkyl comprises 1 carbon atom (eg, C ₁ alkyl). In other embodiments, alkyl comprises 5 to 15 carbon atoms (eg, C _5-15 alkyl). In another embodiment, the alkyl comprises 5-10 carbon atoms (eg, C _5-10 alkyl). In another embodiment, the alkyl comprises 5-8 carbon atoms (eg, C _5-8 alkyl). In other embodiments, alkyl comprises 2 to 5 carbon atoms (eg, C _2-5 alkyl). In other embodiments, alkyl comprises 3-5 carbon atoms (eg, C _3-5 alkyl). In another embodiment, the alkyl group is methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl). ), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR ^a , _{^{-SR a, -OC (O) -R}} a, -N (R a) 2, -C (O) R a, -C (O) OR a, -C (O) N (R a) 2, - _{^{N (R a) C (O}} ) OR a, -OC (O) -N (R a) 2, -N (R a) C (O) R a, -N (R a) S (O) t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t ^Ra (where t is 1). Or 2) and -S(O) _t N(R ^a ) ₂ (where t is 1 or 2), wherein each R ^a is independently hydrogen, alkyl (where By halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally, Halogen, hydroxy, methoxy, or trifluoromethyl substituted), aryl (optionally halogen, hydroxy, methoxy, or trifluoromethyl substituted), aralkyl (optionally halogen, hydroxy, methoxy, or trifluoromethyl) Fluoromethyl substituted), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , Heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

"Aryl" means a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. Aromatic mono- or polycyclic hydrocarbon ring systems contain only hydrogen and carbons of 5 to 18 carbon atoms, wherein at least one ring in the ring system is fully unsaturated, ie , This ring system contains a cyclic delocalized (4n+2)π-electron system according to Huckel theory. The ring system from which the aryl group is derived includes, but is not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. In this specification, unless stated otherwise specifically, the term "aryl" or the prefix "ar-" (such as in "aralkyl") refers to alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, where Optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl. , optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally, optionally substituted ^{heteroarylalkyl, -R b -OR a, -R b} -OC (O) -R a, -R b -OC _{^{(O) -OR a, -R b}} -OC (O) -N (R a) 2, -R b -N (R a) 2, -R b -C (O) R a, -R b -C _{^{(O) OR a, -R b}} -C (O) N (R a) 2, -R b -O-R c -C (O) N (R a) 2, -R b -N (R a) C(O)OR ^a , -R ^b -N(R ^a )C(O)R ^a , -R ^b -N(R ^a )S(O) _t R ^a (where t is 1 or 2). _{^{), - R b -S (O}} ) t R a ( wherein, t is 1 or _{^{2), - R b -S (}} O) t oR a ( wherein, t is 1 or 2) and -R ^b -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) containing an aryl radical optionally substituted with one or more substituents independently selected. Means each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally halogen, hydroxy, Methoxy or trifluoromethyl substituted, cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally halogen, hydroxy, methoxy or trifluoromethyl) , Aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally halogen, hydroxy, methoxy, if Or optionally substituted with trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally with halogen, hydroxy, methoxy, or trifluoromethyl). Substituted), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R ^b is independently a direct bond or a linear or branched alkylene or alkenylene chain. And R ^c is a linear or branched alkylene or alkenylene chain, where each of the above substituents is unsubstituted unless otherwise noted.

"Alkenyl" means a straight or branched hydrocarbon chain radical group containing at least one carbon-carbon double bond and having 2 to 12 carbon atoms and consisting solely of carbon and hydrogen atoms. In certain embodiments, alkenyl comprises 2-8 carbon atoms. In another embodiment, alkenyl comprises 2-4 carbon atoms. Alkenyl is attached to the rest of the molecule by a single bond, eg ethenyl (ie vinyl), prop-1-enyl (ie allyl), but-1-enyl, pent-1-enyl, penta-1,4. -Dienyl and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR ^a , _{^{-SR a, -OC (O) -R}} a, -N (R a) 2, -C (O) R a, -C (O) OR a, -C (O) N (R a) 2, - _{^{N (R a) C (O}} ) OR a, -OC (O) -N (R a) 2, -N (R a) C (O) R a, -N (R a) S (O) t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t ^Ra (where t is 1). Or 2) and -S(O) _t N(R ^a ) ₂ (where t is 1 or 2), wherein each R ^a is independently hydrogen, alkyl (where By halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally, Halogen, hydroxy, methoxy, or trifluoromethyl substituted), aryl (optionally halogen, hydroxy, methoxy, or trifluoromethyl substituted), aralkyl (optionally halogen, hydroxy, methoxy, or trifluoromethyl) Fluoromethyl substituted), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , Heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

"Alkynyl" means a straight or branched hydrocarbon chain radical radical containing only carbon and carbon atoms and containing at least one carbon-carbon triple bond and having 2 to 12 carbon atoms. In certain embodiments, alkynyl comprises 2-8 carbon atoms. In another embodiment, an alkynyl comprises 2-4 carbon atoms. Alkynyl is attached to the rest of the molecule by a single bond and includes, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like. Unless stated otherwise specifically in the specification, an alkynyl group optionally includes one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR ^a , _{^{-SR a, -OC (O) -R}} a, -N (R a) 2, -C (O) R a, -C (O) OR a, -C (O) N (R a) 2, - _{^{N (R a) C (O}} ) OR a, -OC (O) -N (R a) 2, -N (R a) C (O) R a, -N (R a) S (O) t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t ^Ra (where t is 1). Or 2) and -S(O) _t N(R ^a ) ₂ (where t is 1 or 2), wherein each R ^a is independently hydrogen, alkyl (where By halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally, Halogen, hydroxy, methoxy, or trifluoromethyl substituted), aryl (optionally halogen, hydroxy, methoxy, or trifluoromethyl substituted), aralkyl (optionally halogen, hydroxy, methoxy, or trifluoromethyl) Fluoromethyl substituted), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , Heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

"Alkylene" or "alkylene chain" means a straight or branched divalent carbon having from 1 to 12 carbon atoms, containing no unsaturation, consisting only of carbon and hydrogen, which attaches the remainder of the molecule to a radical group. It means a hydrogen chain, and examples thereof include methylene, ethylene, propylene, and n-butylene. The alkylene chain is attached to the rest of the molecule via a single bond and to the radical group via a single bond. The point of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, alkylene comprises 1-8 carbon atoms (eg, C _1-8 alkylene). In other embodiments, the alkylene comprises 1 to 5 carbon atoms (eg, C _1-5 alkylene). In other embodiments, the alkylene comprises 1-4 carbon atoms (eg, C _1-4 alkylene). In other embodiments, the alkylene comprises 1-3 carbon atoms (eg, C _1-3 alkylene). In another embodiment, the alkylene comprises 1-2 carbon atoms (eg, C _1-2 alkylene). In another embodiment, the alkylene comprises 1 carbon atom (eg, C ₁ alkylene). In other embodiments, the alkylene comprises 5-8 carbon atoms (eg, C _5-8 alkylene). In other embodiments, the alkylene comprises 2-5 carbon atoms (eg, C _2-5 alkylene). In other embodiments, the alkylene comprises 3-5 carbon atoms (eg, C _3-5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain optionally comprises one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR ^a , _{^{-SR a, -OC (O) -R}} a, -N (R a) 2, -C (O) R a, -C (O) OR a, -C (O) N (R a) 2, - _{^{N (R a) C (O}} ) OR a, -OC (O) -N (R a) 2, -N (R a) C (O) R a, -N (R a) S (O) t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t ^Ra (where t is 1). Or 2) and -S(O) _t N(R ^a ) ₂ (where t is 1 or 2), wherein each R ^a is independently hydrogen, alkyl (where By halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted by halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally, Halogen, hydroxy, methoxy, or trifluoromethyl substituted), aryl (optionally halogen, hydroxy, methoxy, or trifluoromethyl substituted), aralkyl (optionally halogen, hydroxy, methoxy, or trifluoromethyl) Fluoromethyl substituted), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , Heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

“Aralkyl” means a radical of the formula —R ^c -aryl, where R ^c is an alkylene chain as defined above and includes, for example, methylene, ethylene and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for the alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

“Aralkenyl” means a radical of the formula —R ^d -aryl, where R ^d is an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

“Aralkynyl” means a radical of the formula —R ^e -aryl, where R ^e is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

"Carbocyclyl" means a stable non-aromatic mono- or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, including fused or bridged ring systems, having 3 to 15 carbon atoms. In certain embodiments, carbocyclyl comprises 3 to 10 carbon atoms. In another embodiment, carbocyclyl comprises 5-7 carbon atoms. Carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl can be saturated (ie, containing only a single C—C bond) or unsaturated (ie, containing one or more double or triple bonds). A fully saturated carbocyclyl radical is also referred to as "cycloalkyl". Examples of monocyclic cycloalkyl include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated carbocyclyl is also referred to as "cycloalkenyl". Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (ie bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. . Unless specifically stated otherwise herein, the term "carbocyclyl" refers to alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted Aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted ^{heteroarylalkyl, -R b -OR a, -R b} -OC (O) -R a, -R b -OC (O) -OR a, -R b - _{^{OC (O) -N (R a}} ) 2, -R b -N (R a) 2, -R b -C (O) R a, -R b -C (O) OR a, -R b -C _{^{(O) N (R a)}} 2, -R b -O-R c -C (O) N (R a) 2, -R b -N (R a) C (O) OR a, -R b - ^{N (R a) C (O} ) R a, -R b -N (R a) S (O) t R a ( wherein, t is 1 or ^{2), - R b -S (} O) t R ^a (where t is 1 or 2), -R ^b -S(O) _t OR ^a (where t is 1 or 2) and -R ^b -S(O) _t N ( R ^a ) _2, where t is 1 or 2, is meant to include carbocyclyl radicals optionally substituted with one or more substituents independently selected from R ^{a ).} Are independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). ), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (if optional) Substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally with halogen, hydroxy, methoxy, or trifluoromethyl). Substituted), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or A heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R ^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R ^c is a linear or branched alkylene or alkenylene chain, where each of the above substituents is unsubstituted unless otherwise noted.

“Fluoroalkyl” means an alkyl radical as defined above substituted with one or more fluoro radicals as defined above, eg trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trialkyl. Fluoroethyl, 1-fluoromethyl-2-fluoroethyl and the like can be mentioned. The alkyl part of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group.

“Halo” or “halogen” means a bromo, chloro, fluoro or iodo substituent.

"Heterocyclyl" means a stable 3-18 membered non-aromatic ring radical comprising 2-12 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, a heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. The heteroatoms in the heterocyclyl radical can optionally be oxidized. One or more nitrogen atoms, if present, are optionally quaternized. Heterocyclyl radicals are partially or fully saturated. The heterocyclyl may be attached to the rest of the molecule via any atom of the ring. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl. , Octahydroindolyl, kutahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl. , Tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specifically stated herein, the term "heterocyclyl" refers to alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted Aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted ^{heteroarylalkyl, -R b -OR a, -R b} -OC (O) -R a, -R b -OC (O) -OR a, -R b - _{^{OC (O) -N (R a}} ) 2, -R b -N (R a) 2, -R b -C (O) R a, -R b -C (O) OR a, -R b -C _{^{(O) N (R a)}} 2, -R b -O-R c -C (O) N (R a) 2, -R b -N (R a) C (O) OR a, -R b - ^{N (R a) C (O} ) R a, -R b -N (R a) S (O) t R a ( wherein, t is 1 or ^{2), - R b -S (} O) t R ^a (where t is 1 or 2), -R ^b -S(O) _t OR ^a (where t is 1 or 2) and -R ^b -S(O) _t N ( R ^a ) ₂ (where t is 1 or 2) is meant to include a heterocyclyl radical as defined above optionally substituted with one or more substituents selected from R 1 ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). ), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl ( Optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally halogen, hydroxy, methoxy, or trifluoro) Methyl-substituted), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , Or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R ^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and , R ^c is a linear or branched alkylene or alkenylene chain, wherein each of the above substituents is unsubstituted unless otherwise specified.

“Heterocyclylalkyl” means a radical of the formula —R ^c -heterocyclyl, where R ^c is an alkylene chain as defined above. When the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

"Heteroaryl" means a radical derived from a 3-18 membered aromatic ring radical comprising 2-17 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, a heteroaryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system wherein at least one ring in the ring system is fully unsaturated. Some, ie, this ring system contains a cyclic delocalized (4n+2)π-electron system according to Huckel theory. Heteroaryl includes fused or bridged ring systems. One or more heteroatoms in the heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. Heteroaryl is attached to the rest of the molecule through any atom of the ring. Examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothia. Diazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofranyl, benzoxazolyl, benzodioxolyl, benzo Dioxynyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a] ] Pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5, 6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2] -C]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6 , 7,8,9,10-Hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,6. 7,8-Tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl , 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[ 3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquino Linyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8 ,9-Tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl , Triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (ie thienyl). In this specification, unless stated otherwise specifically, the term "heteroaryl" is alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted. Aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, heteroaryl optionally substituted, optionally substituted ^{heteroarylalkyl, -R b -OR a, -R b} -OC (O) -R a, -R b -OC (O) - _{^{OR a, -R b -OC (O}} ) -N (R a) 2, -R b -N (R a) 2, -R b -C (O) R a, -R b -C (O) OR _{^{a, -R b -C (O)}} N (R a) 2, -R b -O-R c -C (O) N (R a) 2, -R b -N (R a) C (O) ^{oR a, -R b -N (R} a) C (O) R a, -R b -N (R a) S (O) t R a ( wherein, t is 1 or 2), - R _{^{b -S (O) t R a}} ( wherein, t is 1 or _{^{2), - R b -S (}} O) t oR a ( wherein, t is 1 or 2) and -R ^b - Comprising a heteroaryl radical as defined above optionally substituted with one or more substituents selected from S(O) _t N(R ^a ) _2, where t is 1 or 2. Means each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally halogen, hydroxy, Methoxy or trifluoromethyl substituted, cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally halogen, hydroxy, methoxy or trifluoromethyl) , Aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally halogen, hydroxy) , Substituted with methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally halogen, hydroxy, methoxy, or trifluoro) Methyl substituted), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R ^b is independently a direct bond or a straight chain or branched alkylene or It is an alkenylene chain and R ^c is a linear or branched alkylene or alkenylene chain, wherein each of the above substituents is unsubstituted unless otherwise specified.

"Tautomer" means a molecule that is capable of transferring a proton from one atom of the molecule to another atom of the same molecule. The compounds provided herein may exist as tautomers in certain embodiments. In situations where tautomerization is possible, a chemical equilibrium of tautomers will exist. The exact ratio of tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

“In some cases” or “in some cases” means that the subsequently described event or situation may or may not occur, and that the description is an illustration of when the event or situation occurs and no event or situation Is meant to include examples. For example, "optionally substituted aryl" means that the aryl radical may be substituted or unsubstituted and that the description includes both substituted and unsubstituted aryl radicals. means.

"Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the substituted heterocyclic derivative compounds described herein is meant to include any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

“Pharmaceutically acceptable acid addition salts” are those that retain the biological effectiveness and properties of the free base and are not biologically or otherwise undesirable, such as hydrochloric acid, hydrobromic acid, sulfuric acid, By their salts formed with inorganic acids such as nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid. Also included are salts formed with organic acids such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, such as acetic acid, Trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid , P-toluenesulfonic acid, salicylic acid and the like. Thus, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates. Salt, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, Fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate Acid salts, lactates, malates, tartrates, methanesulfonates and the like are included. Also contemplated are salts of amino acids such as alginates, gluconates, and galacturonates (eg, Berge SM et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1-19 (1997). reference). Acid addition salts of basic compounds may be prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt according to methods and techniques well known to those skilled in the art.

"Pharmaceutically acceptable base addition salt" means those salts which retain the biological effectiveness and properties of the free acid, which are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. Pharmaceutically acceptable base addition salts can be formed with metals or amines such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and salts of base ion exchange resins. , For example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N- Dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resin and the like can be mentioned. .. See Berge et al., supra.

Unless otherwise stated, structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having this structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of carbon by ¹³ C or ¹⁴ C-enriched carbon are within the scope of this disclosure.

The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, compounds are, for example, deuterium ⁽² H), tritium ⁽³ H), can be labeled with iodine -125 ⁽¹²⁵ I) or isotope such as carbon -14 ⁽¹⁴ C). ² H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ C, ¹² N, ¹³ N, ¹⁵ N, ¹⁶ N, ¹⁶ O, ¹⁷ O, ¹⁴ F, ¹⁵ F, ¹⁶ F, ¹⁷ F, ¹⁸ F, ³³ S , ³⁴ S, ³⁵ S, ³⁶ S, ³⁵ Cl, ³⁷ Cl, ⁷⁹ Br, ⁸¹ Br, ¹²⁵ I, all isotopic substitutions are contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

In certain embodiments, the compounds disclosed herein have some or all of the ¹ H atoms replaced with ² H atoms. Methods for synthesizing deuterium-containing substituted heterocycle derivative compounds are known in the art and are merely non-limiting examples and include the following synthetic methods.

“Leaving group” is defined as the term will be understood by those skilled in the art, ie, a group on a carbon in which a new bond is formed during the reaction and the carbon loses the group upon formation of the new bond. A typical example of using a suitable leaving group is, for example, on a sp ³ hybridized carbon (S _N 2 or S _N 1 ), for example, the leaving group is a halide, such as a bromide, and the reactant is an odor. Is a nucleophilic substitution reaction which may be benzyl chloride. Another typical example of such a reaction is the nucleophilic aromatic substitution reaction (SNAr). Another example is an insertion reaction (eg, by a transition metal) into a bond between aromatic reaction partners having a leaving group, followed by reductive coupling. “Leaving groups” are not limited to such mechanistic restrictions. Examples of suitable leaving groups include halogen (fluorine, chlorine, bromine or iodine), optionally substituted aryl sulfonates or alkyl sulfonates, aryl phosphonates or alkyl phosphonates, aryl azides or alkyl azides and -S. (O) _0-2 R is included where R is, for example, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl. One skilled in the art of organic synthesis will readily identify suitable leaving groups to carry out the desired reaction under different reaction conditions. Non-limiting features and examples of leaving groups are described, for example, in Organic Chemistry, Second Edition, Francis Carey (1992), pp. 328-331; Introduction to Organic Chemistry, Second Edition, Andrew Streitwieser and Clayton Heathcock (1981), 169. -171; and Organic Chemistry, 5th Edition, John McMurry, Brooks/Cole Publishing (2000), 398 and 408, all of which are incorporated herein by reference. ..

"Protecting group" means a group of atoms which, when attached to a reactive functional group in a molecule, masks, reduces or prevents reactivity of the functional group. In general, protecting groups may be selectively removed during the synthetic process, if desired. Examples of protecting groups are Wuts and Greene, “Greene's Protective Groups in Organic Synthesis,” 4th edition, Wiley Interscience (2006), and Harrison et al., Compendium of Synthetic Organic Methods, Volume 1-8, 1971-1996. , John Wiley & Sons, NY. Functional groups that can have protecting groups include, but are not limited to, hydroxy, amino, and carboxy groups. Representative amine protecting groups include, but are not limited to, formyl, acetyl (Ac), trifiuoroacetyl, benzyl (Bn), benzoyl (Bz), carbamate, benzyloxycarbonyl (“ CBZ"), p-methoxybenzylcarbonyl (Moz or MeOZ), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("SES"), trityl and substituted trityl groups, allyl. Included are oxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl (“NVOC”), p-methoxybenzyl (PMB), tosyl (Ts) and the like.

"Solvates" may include, but are not limited to, solvates that retain one or more of the activity and/or properties of the compound and are not undesired. Examples of solvates include, but are not limited to, compounds in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, ethanolamine, or combinations thereof.

"Salts" can include, but are not limited to, salts that retain one or more of the activities and properties of the free acid and free base, and are not undesirable. Illustrative examples of salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates. , Metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, capronate, heptate , Propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate Acid salt, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, Phenyl butyrate, citrate, lactate, y-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, And mandelate.

"Solvent" can include, but is not limited to, nonpolar, polar aprotic, and polar protic solvents. Illustrative examples of non-polar solvents include, but are not limited to, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, chloroform, diethyl ether, and dichloromethane (DCM). Be done. Illustrative examples of polar aprotic solvents include, but are not limited to, tetrahydrofuran (THF), ethyl acetate, acetone, dimethylformamide (DMF), acetonitrile (MeCN), dimethylsulfoxide (DMSO), nitromethane, And propylene carbonate. Illustrative examples of polar protic solvents include, but are not limited to, formic acid, n-butanol, isopropanol (IPA), n-propanol, ethanol, methanol, acetic acid, and water.

The "transition metal" includes, but is not limited to, scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium. , Silver, cadmium, hafnium, tantalum, tungsten, rhenium, osmium, iridium, platinum, gold, mercury, rutherfordium, dovnium, seaborgium, bolium, hassium, mitnerium, unununilium, unununium, and ununbium.

“Acid” means a molecule or ion that can donate a hydron (proton or hydrogen ion H+) or can form a covalent bond with an electron pair (eg, a Lewis acid). Acids can include, but are not limited to, mineral acids, sulfonic acids, carboxylic acids, halogenated carboxylic acids, vinylic carboxylic acids, and nucleic acids. Illustrative examples of mineral acids include, but are not limited to, hydrogen halides and their solutions: hydrofluoric acid (HF), hydrochloric acid (HCl), hydrobromic acid (HBr), hydrogen iodide. Acid (HI); halogen oxo acids: hypochlorous acid (HClO), chlorous acid (HClO ₂ ), chloric acid (HClO ₃ ), perchloric acid (HClO ₄ ), and analogues corresponding to bromine and iodine, And hypofluorous acid (HFO); sulfuric acid (H ₂ SO ₄ ); fluorosulfuric acid (HSO ₃ F); nitric acid (HNO ₃ ); phosphoric acid (H ₃ PO ₄ ); fluoroantimonic acid (HSbF ₆ ); fluoroboric acid (HBF ₄ ); hexafluorophosphoric acid (HPF ₆ ); chromic acid (H ₂ CrO ₄ ); and boric acid (H ₃ BO ₃ ). Illustrative examples of sulfonic acids include, but are not limited to, methane sulfonic acid (or mesylic acid, CH ₃ SO ₃ H), ethane sulfonic acid (or ethylic acid, CH ₃ CH ₂ SO ₃ H), benzenesulfonic acid (or _{besylate, C 6 H 5 SO 3 H} ), p- toluenesulfonic acid (or _{tosylate, CH 3 C 6 H 4 SO} 3 H), trifluoromethanesulfonic acid (or triflic acid, _CF 3 SO ₃ H), and polystyrene sulfonic acid (sulfonated polystyrene, [CH ₂ CH(C ₆ H ₄ )SO ₃ H] _n ). Illustrative examples of carboxylic acids include, but are not limited to, acetic acid _(CH 3 COOH), citric acid _{(C 6 H 8 O 7)} , formic acid (HCOOH), gluconic acid _(HOCH 2 - _{(CHOH) 4} -COOH), lactic acid _(CH 3 -CHOH-COOH), oxalate (HOOC-COOH), and tartaric acid (HOOC-CHOH-CHOH-COOH ) is. Illustrative examples of halogenated carboxylic acids include, but are not limited to, fluoroacetic acid, trifluoroacetic acid, chloroacetic acid, dichloroacetic acid, and trichloroacetic acid. Illustrative examples of vinylic carboxylic acids include, but are not limited to, ascorbic acid. Illustrative examples of nucleic acids include, but are not limited to, deoxyribonucleic acid (DNA) and ribonucleic acid (RNA).

"Base", can receive a proton from a proton donor, and / or hydroxide ions (OH ^-) means a molecule or ion capable of producing. Illustrative examples of bases include, but are not limited to, aluminum hydroxide (Al _(OH) 3), ammonium hydroxide _(NH 4 OH), hydroxide arsenic (As _{(OH) 3),} hydroxide Barium (Ba(OH) ₂ ), beryllium hydroxide (Be(OH) ₂ ), bismuth (III) hydroxide (Bi(OH) ₃ ), boron hydroxide (B(OH) 3 ), cadmium hydroxide (Cd) (OH) ₂ ), calcium hydroxide (Ca(OH) ₂ ), cerium (III) hydroxide (Ce(OH) ₃ ), cesium hydroxide (CsOH), chromium hydroxide (II) (Cr(OH) ₂ ), chromium (III) hydroxide (Cr(OH) ₃ ), chromium (V) hydroxide (Cr(OH) ₅ ), chromium (VI) hydroxide (Cr(OH) ₆ ), cobalt (II) hydroxide (Co(OH) ₂ ), cobalt (III) hydroxide (Co(OH) ₃ ), copper(I) hydroxide (CuOH), copper(II) hydroxide (Cu(OH) ₂ ), gallium hydroxide ( II) (Ga(OH) ₂ ), gallium hydroxide (III) (Ga(OH) ₃ ), gold (I) hydroxide (AuOH), gold hydroxide (III) (Au(OH) ₃ ), hydroxylation Indium (I) (InOH), indium (II) hydroxide (In(OH) ₂ ), indium (III) hydroxide (In(OH) ₃ ), iridium (III) hydroxide (Ir(OH) ₃ ), Iron hydroxide (II) (Fe(OH) ₂ ), iron hydroxide (III) (Fe(OH) ₃ ), lanthanum hydroxide (La(OH), lead hydroxide (II) (Pb(OH) ₂ ). , Lead hydroxide (IV) (Pb(OH) ₄ ), lithium hydroxide (LiOH), magnesium hydroxide (Mg(OH) ₂ ), manganese hydroxide (II) (Mn(OH) ₂ ), manganese hydroxide (III) (Mn(OH) ₃ ), manganese (IV) hydroxide (Mn(OH) ₄ ), manganese hydroxide (VII) (Mn(OH) ₇ ), mercury (I) hydroxide (Hg ₂ (OH ) ₂ ), mercury (II) hydroxide (Hg(OH) ₂ ), molybdenum hydroxide (Mo(OH) ₃ ), neodymium hydroxide (Nd(OH) ₃ ), nickel oxohydroxide (NiOOH), hydroxide Nickel (II) (Ni(OH) ₂ ), nickel (III) hydroxide (Ni(OH) ₃ ), niobium hydroxide (Nb(OH) ₃ ), osmium hydroxide (IV) (Os(OH) ₄ ). , Hydroxylation Palladium (II) (Pd(OH) ₂ ), palladium (IV) hydroxide (Pd(OH) ₄ ), platinum (II) hydroxide (Pt(OH) ₂ ), platinum (IV) hydroxide (Pt(OH) ) ₄ ), plutonium hydroxide (IV) (Pu(OH) ₄ ), potassium hydroxide (KOH), radium hydroxide (Ra(OH) ₂ ), rubidium hydroxide (RbOH), ruthenium hydroxide (III) ( Ru(OH) ₃ ), scandium hydroxide (Sc(OH) ₃ ), silicon hydroxide (Si(OH) ₄ ), silver hydroxide (AgOH), sodium hydroxide (NaOH), strontium hydroxide (Sr(OH) ) ₂ ), tantalum (V) hydroxide (Ta(OH) ₅ ), technetium (II) hydroxide (Tc(OH) ₂ ), tetramethylammonium hydroxide (C ₄ H ₁₂ NOH), thallium hydroxide (I). )(TlOH), thallium(III) hydroxide (Tl(OH) ₃ ), thorium hydroxide (Th(OH) ₄ ), tin(II) hydroxide (Sn(OH) ₂ ), tin(IV) hydroxide. (Sn(OH) ₄ ), titanium (II) hydroxide (Ti(OH) ₂ ), titanium (III) hydroxide (Ti(OH) ₃ ), titanium hydroxide (IV) (Ti(OH) ₄ ), Tungsten (II) hydroxide (W(OH) ₂ ), uranyl hydroxide ((UO ₂ ) ₂ (OH) ₄ ), vanadium hydroxide (II) (V(OH) ₂ ), vanadium hydroxide (III) ( V(OH) ₃ ), vanadium hydroxide (V) (V(OH) ₅ ), ytterbium hydroxide (Yb(OH) ₃ ), yttrium hydroxide (Y(OH) ₃ ), zinc hydroxide (Zn(OH) ) ₂ ) and zirconium hydroxide (Zr(OH) ₄ ).

In certain embodiments, the methods disclosed herein can be performed simultaneously, in the sequential order described herein, or in any possible order thereof.

In certain embodiments of the method, the temperature of the disclosed reaction can be selected to maximize the reaction rate at higher temperatures while maintaining the activity of the reaction for efficient synthesis. In a particular embodiment, the reaction is about 5-150°C, for example about 5-150°C, about 5-130°C, about 5-110°C, about 5-90°C, about 5-70°C, about 5-5°C. 50°C, about 5-30°C, about 5-10°C, about 10-150°C, about 10-130°C, about 10-110°C, about 10-90°C, about 10-70°C, about 10-50°C. About 10 to 30°C, about 30 to 150°C, about 30 to 130°C, about 30 to 110°C, about 30 to 90°C, about 30 to 70°C, about 30 to 50°C, about 50 to 150°C, about 50-130°C, about 50-110°C, about 50-90°C, about 50-70°C, about 70-150°C, about 70-130°C, about 70-110°C, about 70-90°C, about 90- It can be carried out at temperatures of 150°C, about 90-130°C, about 90-110°C, about 110-150°C, about 110-130°C, or about 130-150°C.

Method for Producing Compounds of Formula (1) and (4) In the present specification, formula (1):
A compound of formula (2):
A compound of formula (3):
A method of contacting with a compound of
R ₁ is H or an amine protecting group;
R ₂ is H, C _1-10 alkyl, C _1-10 haloalkyl, or aryl; and each R ₃ is independently H, halogen, C _1-10 alkyl, C _1-10 haloalkyl, or aryl. Is]
Is disclosed.

In some embodiments, the compound of formula (1) or salt thereof has the formula (4):
It has the structure of.

Method for Producing Compounds of Formulas (5) and (6) In this specification, formula (5):
A compound of formula (1):
A compound or salt thereof is contacted with a catalyst, wherein
R ₁ is H or an amine protecting group;
R ₂ is H, C _1-10 alkyl, C _1-10 haloalkyl, or aryl; and each R ₃ is independently H, halogen, C _1-10 alkyl, C _1-10 haloalkyl, or aryl. Is]
Is disclosed.

In some embodiments, the compound of formula (5) or salt thereof has the formula (6):
It has the structure of.

Method for Producing Compounds of Formulas (7) and (8) In this specification, formula (7):
A salt of the formula (5):
A compound or salt thereof is contacted with a metal hydroxide, wherein
R ₁ is H or an amine protecting group;
R ₂ is H, C _1-10 alkyl, C _1-10 haloalkyl, or aryl;
Each R ₃ is independently H, halogen, C _1-10 alkyl, C _1-10 haloalkyl, or aryl; and A is a cation]
Is disclosed.

In some embodiments, the cation is an inorganic or organic cation. In some embodiments, the cation is a metal cation. In some embodiments, the metal cation is an alkali metal cation. In some embodiments, the alkali metal cation is a lithium cation.

In some embodiments, the salt of formula (7) has the formula (8):
It has the structure of.

Method for Producing Compounds of Formulas (9) and (10) In this specification, formula (9):
A compound of formula (7):
A compound or a salt thereof, which is contacted with a coupling reagent and ammonium hydroxide, wherein
R ₁ is H or an amine protecting group;
R ₂ is H, C _1-10 alkyl, C _1-10 haloalkyl, or aryl; each R ₃ is independently H, halogen, C _1-10 alkyl, C _1-10 haloalkyl, or aryl. Yes; and A is a cation]
Is disclosed.

In some embodiments, the cation is a metal cation. In some embodiments, the metal cation is an alkali metal cation. In some embodiments, the alkali metal cation is a lithium cation. In some embodiments, the coupling reagent is CDI.

In some embodiments, the compound of formula (9) or salt thereof has the formula (10):
It has the structure of.

Method for Producing Compounds of Formula (11) and (12) In the present specification, formula (11):
A salt of the formula (9):
And a salt thereof with para-toluenesulfonic acid monohydrate (pTSA.H ₂ O).
R ₁ is H or an amine protecting group;
R ₂ is H, C _1-10 alkyl, C _1-10 haloalkyl, or aryl; and each R ₃ is independently H, halogen, C _1-10 alkyl, C _1-10 haloalkyl, or aryl. Is]
Is disclosed.

In some embodiments, the salt of formula (11) has the formula (12):
It has the structure of.

Method for Producing Enantiomerically Enriched Tosylate (S)-Nilaparib Monohydrate As used herein, formula (12):
A method for producing an enantiomerically enriched tosylate (S)-nilaparib monohydrate of
a) contacting a mixture comprising (R)-niraparib monohydrate tosylate and (S)-niraparib monohydrate tosylate with water and a first organic solvent;
b) separating the tosylate (S)-nilaparib monohydrate from the mixture by filtration to form the enantiomerically enriched tosylate (S)-nilaparib monohydrate; and c) the enantiomerically enriched tosylate ( Contacting S)-nilaparib monohydrate with a second organic solvent, water, or any combination thereof to form a crystalline form of the enantiomerically enriched tosylate (S)-nilaparib monohydrate.
A method comprising is disclosed.

In some embodiments, the method further comprises wet milling the crystalline form of the enantiomerically enriched (S)-nilaparib monohydrate tosylate. In some embodiments, the method further comprises annealing the enantiomerically enriched (S)-nilaparib monohydrate with one or more temperature cycles.

Further, in the present specification, the formula (12):
A method for producing an enantiomerically enriched tosylate (S)-nilaparib monohydrate of
a) Formula (13):
A salt of formula (14) with sodium hydroxide and toluene.
Forming a compound of
b) Formula (15):
By contacting a compound of formula (16) with sodium azide, ethyl acetate and DMSO:
Forming a compound of
c) contacting a compound of formula (14) with a compound of formula (16) and TFA to give formula (4):
Forming a compound of
d) contacting the compound of formula (4) with copper (II) trifluoromethanesulfonate (Cu(OTf) ₂ ), THF and toluene to form formula (6):
Forming a compound of
e) contacting the compound of formula (6) with lithium hydroxide and ethanol to form formula (8):
Forming a salt of;
f) contacting the salt of formula (8) with CDI, TFA, N,N-dimethylformamide (DMF), and ammonium hydroxide to form formula (10):
Forming a compound of
g) contacting the compound of formula (10) with p-toluenesulfonic acid monohydrate (pTSA.H ₂ O) and THF to give formula (12):
Forming (S)-nilaparib monohydrate of:
h) contacting (S)-nilaparib monohydrate of formula (12) with acetonitrile and water to form a mixture;
i) separating the tosylate (S)-nilaparib monohydrate from the mixture by filtration to form the enantiomerically enriched tosylate (S)-nilaparib monohydrate; and j) the enantiomerically enriched tosylate ( Contacting S)-niraparib monohydrate with DMSO and water to form a crystalline form of the enantiomerically enriched (S)-nilaparib monohydrate.
A method comprising is disclosed.

In some embodiments, the method further comprises wet milling the crystalline form of the enantiomerically enriched (S)-nilaparib monohydrate tosylate. In some embodiments, the method further comprises annealing the enantiomerically enriched (S)-nilaparib monohydrate with one or more temperature cycles.

The salts herein of formula (7) and (8), equation (7):
Salt [in the formula,
R ₁ is H or an amine protecting group;
Each R ₃ is independently H, halogen, C _1-10 alkyl, C _1-10 haloalkyl, or aryl; and A is a cation]
Is disclosed.

In some embodiments, the cation is a metal cation. In some embodiments, the metal cation is an alkali metal cation. In some embodiments, the alkali metal cation is a lithium cation.

In some embodiments, the salt of formula (7) has the formula (8):
It has the structure of.

Method for Producing Compound of Formula (17) In the present specification, formula (17):
A compound of formula (18):
Disclosed is a method of contacting a compound of claim 1 or a salt thereof with n-butyllithium and triisopropyl borate (B(Oi-Pr) ₃ ), wherein R ₄ is a leaving group. . In some embodiments, the method further comprises a hydrolysis reaction.

In some embodiments, the method comprises formula (19):
Contacting a compound of formula (18) or a salt thereof with benzoyl chloride and an organic compound to form a compound of formula (18) or salt thereof, wherein R ₄ is a leaving group.

Method for Producing Compounds of Formula (20) and (26) In the present specification, formula (20):
A method for producing the compound or a salt thereof according to formula (17):
A compound of formula (21):
Disclosed is a method comprising contacting the salt of claim 1 with a salt in the presence of a catalyst.

In some embodiments, contacting the compound of formula (17) or a salt thereof comprises contacting a compound of formula (22):
Further comprising contacting the salt of.

In this specification, equation (26):
A method for producing the compound or a salt thereof according to formula (17):
A compound of formula (22):
Disclosed is a method comprising contacting the salt of claim 1 with a salt in the presence of a catalyst.

Method for Producing Compounds of Formula (23) and (24) In the present specification, formula (23):
A method for producing the compound or a salt thereof according to formula (17):
Of the compound or its salt
The method comprising contacting a wherein each R ₅ is independently H or C _1-3 alkyl
Is disclosed.

In some embodiments, the compound of formula (23) or salt thereof has the formula (24):
It has the structure of.

Method for Producing Compounds of Formula (20) and (26) In the present specification, formula (20):
A compound of formula (23):
A compound of formula (21):
Disclosed is a method comprising contacting the salt of claim 1 with a salt in the presence of a catalyst.

In some embodiments, contacting the compound of formula (23) or salt thereof comprises contacting the compound of formula (22):
Further comprising contacting the salt of.

Also herein, equation (26):
A compound of formula (23):
A compound of formula (22):
Disclosed is a method comprising contacting the salt of claim 1 with a salt in the presence of a catalyst.

Method for producing compound of formula (25) In the present specification, formula (25):
A compound of formula (20):
Disclosed is a method comprising contacting a compound of claim 1 or a salt thereof with a ligand.

In some embodiments, the method comprises formula (26):
Further comprising contacting the compound of claim 1 or a salt thereof with a ligand.

Method for producing compound of formula (14) In the present specification, formula (14):
A method for producing the compound or a salt thereof, comprising:
Formula (25)
Disclosed is a method comprising contacting a compound of claim 1 or a salt thereof with a base.

Method for producing salt of formula (13) In the present specification, formula (13):
A salt of the formula (14):
Disclosed is a method comprising contacting a compound of claim 1 or a salt thereof with an acid.

Method for Producing Compounds of Formula (21) and (22) In the present specification, formula (21):
A compound of formula (28):
Of the compound of formula (29):
Forming a compound of formula (29) or a salt thereof; and contacting a compound of formula (29) or salt thereof with p-toluenesulfonic anhydride. In some embodiments, the oxidant is 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO).

In some embodiments, contacting the compound of formula (29) or salt thereof comprises contacting the compound of formula (21) and formula (22):
Resulting in the formation of a mixture of compounds.

Method for Producing Compounds of Formula (30) and (25) In the present specification, formula (30):
Or a salt thereof [wherein
Each R ₁ is independently H or an amine protecting group; and each R ₃ is independently H, halogen, C _1-10 alkyl, C _1-10 haloalkyl, or aryl].
Is disclosed.

In some embodiments, the compound or salt thereof has the formula (25):
It has the structure of.

The following examples illustrate some embodiments and aspects of the invention. Various modifications, additions and substitutions can be made without changing the spirit or scope of the present invention, and such modifications and variations are included together with the invention defined in the following claims. It will be obvious to those skilled in the relevant fields. The invention disclosed herein is further illustrated by the following examples, which should not be construed as limiting in any way.

Example 1-Synthesis of methyl 3-formyl-2-nitrobenzoate (aldehyde A) Example 1 illustrates the synthesis of the compound methyl 3-formyl-2-nitrobenzoate (aldehyde A) (see also Figure 1). ).

A two-step reaction was performed for the synthesis of the compound methyl 3-formyl-2-nitrobenzoate.

Reaction 1.1: Synthesis of methyl-3-(2-(dimethylamino)vinyl)-2-nitrobenzoate

A clean reactor was charged with dimethylformamide (DMF, 530 g) and methyl-3-methyl-2-nitrobenzoate (100.0 g, 1.0 eq). The mixture was stirred and heated to 130°C under nitrogen protection. N,N-Dimethylformamide dimethyl acetal (DMF-DMA, 130 g, equivalent) was added dropwise while maintaining the temperature at 130°C. The mixture was stirred at 130° C. for 16 hours and taken for completion of reaction. Upon completion, the mixture was cooled to 5°C and stirred for 2 hours. The product was isolated by filtration and washed with water (5 x 130 mL). The wet cake (83.3 g, 65%) was used directly in the next step. ¹ H NMR (400 MHz, CDCl3) 7.58 (m, 2H), 7.31 (m, 1H), 6.88 (d, J=13.4 Hz, 1H), 4.94 (d, J=13.4 Hz, 1H) 3.891 (s, 3H), 2.875 (s, 6H).

Reaction 1.2: Synthesis of methyl 3-formyl-2-nitrobenzoate

A clean, dry reactor was charged with DMF (525 g) and crude intermediated from the previous step (83.3 g, 330 mmol, 1.0 eq). The mixture was stirred at 33° C. until all solids had dissolved. The clear liquid was removed and stoppered. Deionized water (640 g) was charged to the reactor and the temperature was adjusted to 30°C. Solid sodium periodate (NaIO4, 149.9 g, 2.1 eq) was added and the temperature adjusted to 45°C. A solution of the enamine intermediate in DMF was charged to an overhead dropping funnel and slowly added to the stirred hydrous sodium periodate. Once the addition was complete, the reaction mixture was stirred at 45° C. for 4 hours. Ethyl acetate (933g) was added and the mixture was stirred at 35°C for 1 hour. The three phase mixture was filtered. The filtrate was transferred to a clean reactor. The filtered solid was slurried with ethyl acetate, the mixture was filtered and the ethyl acetate filtrate was combined with the first filtrate. The combined filtrate was stirred at 35° C. for 30 minutes. The stirring was stopped and the mixture was left for 30 minutes. The layers were separated and the aqueous phase was mixed with ethyl acetate (225g), cooled to 5°C and stirred for 30 minutes. The solid formed was removed by filtration. The layers were separated and this process was repeated. The obtained organic solution was washed twice with an aqueous sodium chloride solution (350 kg 1.5% NaCl). The final organic solution tested negative on iodine starch paper. The organic solution was mixed with activated carbon (20 g) and stirred at 75° C. for 6 hours. The mixture was cooled to 45°C and filtered through diatomaceous earth. The ethyl acetate filtrate was concentrated under reduced pressure (<40° C.) to a final volume of 125-167 mL. The mixture was cooled to 0° C. and stirred for 6 hours. The product was isolated by filtration and dried under vacuum at 25° C. to give aldehyde A as a clean pale yellow solid (56.6 g, 80%). ¹ H NMR (400 MHz, CDCl3) 9.95 (s, 1H), 8.27 (d, J= 8.0 Hz, 1H), 8.16 (d, J= 8.0 Hz, 1H), 7.77 (t, J= 8.0 Hz, 1H ), 3.93 (s, 3H).

Example 2-Synthesis of (S)-4-(1-(tert-butoxycarbonyl)piperidin-3-yl)benzeneaminium ethanesulfonate (aniline ESA salt) Example 2 is compound (S)-4. The synthesis of -(1-(tert-butoxycarbonyl)piperidin-3-yl)benzenaminium ethanesulfonate (aniline ESA salt) is described (see also Figure 2).

A multistep reaction was carried out for the synthesis of the compound (S)-4-(1-(tert-butoxycarbonyl)piperidin-3-yl)benzeneaminium ethanesulfonate (aniline ESA salt).

Reaction S-1: Synthesis of N-(4-bromophenyl)benzamide

4-Bromoaniline (100 g, 581 mmol, 1.0 eq) was charged to a clean reactor. Tetrahydrofuran (THF, 410 mL) was added and the mixture was stirred until a clear liquid formed. Triethylamine (TEA, 60g, 593mmol, 1.02eq) was added and the mixture cooled to about -5°C. Benzoyl chloride (80 g, 569 mmol, 0.98 eq) was added dropwise while maintaining the temperature at about 0°C. The mixture was then stirred at room temperature for 2 hours. Water (1000 g) was gradually added dropwise at room temperature. After stirring at room temperature for 4 hours, the crude solid product was isolated by filtration and the filter cake was washed with water (2 x 200 mL). The wet cake was isolated and dried under vacuum at 50° C. or lower for 40 hours to give 156 g (97%) of N-(4-bromophenyl)benzamide. ¹ H NMR (400 MHz, DMSO-d6) 10.383 (s, 1H), 7.97 (d, J = 8.5, 2H), 7.79 (d, J = 8.5, 2H), 7.61-7.52 (m, 5H)); 13C NMR (DMSO-d6, 100.61 MHz); 166.136, 139.063, 135.191, 132.173, 131.896, 128.884, 128.155, 122.687, 115.797; HRMS m/z: [M + H]+ Calculated value for C13H11BrNO: 276.0019; Found. : 276.0025.

Reaction S-2: Synthesis of (4-benzamidophenyl)boronic acid

The reactor was charged with N-(4-bromophenyl)benzamide (100 g, 362 mmol, 1.0 eq) and THF (2090 mL). The mixture was stirred at about 25°C until the solids dissolved, then cooled to about -85 to -70°C. In a separate reactor, 2.5 n-butyllithium in hexane (104 g, 375 mmol, 1.0 eq) was added slowly to a solution of bromoaniline in THF while maintaining the internal temperature between -85 and -70 °C. Was filled. The resulting mixture was stirred at -85°C and -70°C for an additional 30 minutes. A second portion of 2.5n-n-butyllithium (149g, 538mmol, 1.5eq) in hexane, maintaining the internal temperature between -85 and -70°C. After the addition was complete, the mixture was stirred at about −85 to −70° C. for about 30 minutes and triisopropyl borate (270 g, 1.4 mol, 4.0 eq) was added while maintaining the temperature at −85 to −70° C. Gradually added. The mixture was then stirred at -85 to -70°C until the reaction reached completion. Acetic acid (200 g, 3.3 mol, 9.1 eq) was added while maintaining the temperature between -10 and 10 <0>C. The mixture was stirred at 0° C. for 4 hours (pH about 5) and concentrated under reduced pressure (about 45° C.) to (550 mL, 5.5 V). The temperature of the mixture was adjusted to 20° C. and water (1050 mL) was added. The mixture was stirred at 20° C. for 4 hours and the resulting crude solid product was isolated by filtration. The crude product (about 146 g) was charged to the reactor with water (650 g) and methyl t-butyl ether (MTBE, 450 g). The slurry was stirred at 20° C. for about 4 hours. The mixture was filtered and the resulting solid washed successively with water and MTBE. The filter cake was dried under vacuum at about 55° C. for 48 hours to give 80 g (92%) of the desired boronic acid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 10.251 (s 1H), 7.94 (d, J=7.2, 4H), 7.74 (d, J=3.2, 4H), 7.58-7.54 (m, 1H); ¹³ C NMR (DMSO-d ₆ , 100.61 MHz); 166.085, 141.309, 135.461, 135.184, 132.042, 128.855, 128.141, 119.508; HRMS m/z: [M + H] ⁺ calculated for C ₁₃ H ₁₃ BNO ₃ : 241.1019; Found: 241.1015.

Reaction S-3 (optional step): Synthesis of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide

The reactor was charged with THF (720 g), then the boronic acid intermediate ((4-benzamidophenyl)boronic acid) (100 g, 1.0 eq), and pinacol (60 g, 1.2 eq). The mixture was stirred and heated to 65° C. for 4 hours. The mixture was heated to 75° C. and concentrated at atmospheric pressure to 4.0 volume (V). The mixture was cooled to 50° C. and concentrated under reduced pressure at about 50° C. to 2.0V. N-Heptane (1030 mL) was added slowly while maintaining the temperature at 50°C. The mixture was stirred at 50° C. for 3 hours, cooled to 5° C. over 2 hours and stirred at 5° C. for 6 hours. The product was isolated by filtration and washed with n-heptane. The wet cake was dried under vacuum at 45° C. to give the desired product as an off-white solid (139 g, 100%). ¹ H NMR (400 MHz, CDCl ₃ ) 7.89 (d, J=7Hz, 3H), 7.85 (d, J=8Hz, 2H), 7.70 (d, J=8Hz, 2H), 7.57 (d, J=7Hz , 2H), 7.28 (dd, J=7Hz, J=8Hz, 2H), 1.374 (s, 12H); ¹³ C NMR (DMSO-d ₆ ,100.61 MHz); 166.201, 142.541, 135.607, 135.301, 132.144, 128.863. , 128.192, 119.741, 83.948, 25.173; HRMS m/z: [M + H] ⁺ C ₁₉ H ₂₂ Calculated value for BNO ₃ : 323.1802; Found value: 323.1798.

Reaction S-9: tert-butyl 5-(tosyloxy)-3,4-dihydropyridine-1(2H)-carboxylic acid and tert-butyl 5-(tosyloxy)-3,6-dihydropyridine-1(2H)-carboxylic acid Synthesis of

A clean reactor was charged with DCM (800 g) and 1-Boc-3-hydroxypiperidine (100 g, 1.0 eq). The mixture was stirred and cooled to 0°C. Aqueous sodium bicarbonate solution was added (500g) and the mixture was stirred at 0°C. Solid potassium bromide (2 g, 0.03 equiv) was added while maintaining the temperature at about 5°C. 2,2,6,6-Tetramethylpiperidine-1-oxyl (TEMPO, 100 mg, 0.001 eq) was added and the mixture was left at 0° C. for 30 minutes. Hydrous sodium hypochlorite (10%, 450 g, 1.2 eq) was added slowly at 0° C. over 5 hours. After the addition was complete, the mixture was stirred at 0° C. for 30 minutes. Hydrous sodium sulfite (20% 490 g, 1.6 eq) was added at 0° C. over 1 hour, the mixture was stirred at 0° C. for 40 minutes, left to stand and the layers separated. The aqueous phase was extracted twice with DCM (500 g) at 0° C. and the combined organic phases were washed with water (500 g) at 0° C. The layers were separated and the organic phase was concentrated by vacuum distillation to 450 mL at about 25° C. before DCM (670 mL) was added. The solution was cooled and used directly in the next step.

The mixture prepared above was cooled and DCM (670 g) was added. p-Toluenesulfonic anhydride (180 g, 1.1 eq) was added slowly at 0° C., then trimethylamine (TEA 95 g, 1.9 eq) was also added slowly at 0° C. The mixture was stirred at 0° C. for 1 hour. After warming to 25° C., the mixture was stirred for 14 hours. The mixture was then cooled to 5° C., water (530 g) was added at 5° C. over 1 hour and the mixture was stirred at 5° C. for 1 hour. The layers were separated and the organic phase was washed twice with water (300g). The organic phase was treated with activated carbon (10 g) in DCM (40 g). After stirring for 4 hours at room temperature, the mixture was filtered through a layer of silica gel (5 g). The filtrate was washed twice with water (310 g) and concentrated by vacuum distillation at about 50° C. to 250 mL. Isopropyl alcohol (430 g) was added and the mixture was concentrated under vacuum at about 50° C. to 250 mL. The temperature was adjusted to 50° C. and the mixture was stirred until a clear liquid was formed. Water (290 g) was added slowly at 50° C. over 3 hours, the mixture was stirred at 50° C. for 90 minutes, then cooled to 15° C. over 6 hours, and left to stand for another 6 hours. The crude product was isolated by filtration and the filter cake washed with IPA/water (1:2 w/w, 10 g). The wet cake was returned to the reactor and slurried with 220 mL of IPA/water (1:2 w/w) mixture at 15° C. for 30 minutes. The product was isolated by vacuum filtration, washed with IPA/water (1:2 w/w, 10 g) and dried under vacuum at 45° C. to give the desired product (134.8 g, 77%). .. ¹ H NMR (400 MHz, CDCl ₃ ) 7.82 (d, 2H), 7.35 (d, 2H), 6.75 (s, 0.3H) 6.48 (s, 0.7H), 3.42 (t, J= 5.6, 2H), 2.46 (s, 3H), 2.30 (m, 2H), 1.81 (t, J=5.6, 2H), 1.40 (s, 9H); ¹³ C NMR (CDCl3, 100.61 MHz); 151.560, 145.086,133.004, 132.362, 129.847, 129.723, 128.534, 128.359, 121.199, 120.654, 81.243, 41.761, 40.580, 28.352, 28.134, 25.290, 21.710, 21.134, 20.828; HRMS m/z: [M + NH ₄ ] ⁺ C ₁₇ H ₂₇ N ₂ O ₅ Calculated value for S: 371.1635; Found: 371.1632.

Reaction S-4: tert-Butyl 5-(4-benzamidophenyl)-3,6-dihydropyridine-1(2H)-carboxylate and 5-(4-benzamidophenyl)-3,4-dihydropyridine-1(2H). -Synthesis of tert-butyl carboxylate

In the reactor, the tosylate intermediates (tert-butyl 5-(tosyloxy)-3,4-dihydropyridine-1(2H)-carboxylate and 5-(tosyloxy)-3,6-dihydropyridine-1(2H)- Charged tert-butyl carboxylate, 112 g, 317 mmol, 1.00 eq) and THF (884 mL). The temperature of the mixture was adjusted to 20° C. and the boronic acid derivative (80.0 g, 332 mmol, 1.05 eq) was added, followed by an aqueous potassium phosphate (30%, 571 g) solution. XPhos (680 mg, 0.005 equiv) was added and the reaction mixture was deoxygenated by 5 vacuum/nitrogen purge cycles. Palladium acetate (224 mg, 0.004 eq) was added, followed by another vacuum/nitrogen purge cycle. The mixture was stirred and maintained at 65°C for 10 hours. After adjusting the temperature to 25° C., the phases were separated and the organic phase was concentrated under vacuum to about 250 mL before DCM (1050 mL) was added. The resulting mixture was stirred at room temperature for about 2 hours and then filtered through a filter aid, diatomaceous earth. The filtrate was washed twice with water. The organic phase was treated with activated carbon (18g). The mixture was stirred at 25° C. for 2 hours and filtered through diatomaceous earth to give a clear liquid. The solution was concentrated under reduced pressure (internal temperature below 50° C.) to approximately 300 mL. 2-Me THF (440 mL) was added and the mixture was concentrated under reduced pressure (internal temperature <50 °C). n-Heptane (1450 mL) was added and the mixture was stirred at 45°C then about 15°C for about 2 hours. The product was isolated by filtration and the filter cake was washed with a mixture of 2-MeTHF/n-heptane (1:3 v/v) then n-heptane. The wet product was dried under vacuum at 40-60° C. to give 92 g (86.2%). ¹ H NMR (400 MHz, CDCl ₃ ) 8.20 (br s, 1H), 7.87 (d, 2H), 7.64-7.33 (mm, 8H), 6.19 (br s, 0.13H), 4.23 (br s, 0.27H ), 3.58 (m, 2H), 2.44 (br s, 2H), 1.97 (br s, 2H), 1.55 (s, 9H); ¹³ C NMR (CDCl ₃ ,100.61 MHz); 165.822, 165.742, 155.024, 152.960 , 152.443, 136.081, 135.0.46, 131.735, 128.717, 127.
076, 125.560, 124.867, 124.0634, 122.847, 122.505, 120.383, 120.281, 115.818, 81.054,80.893, 42.293, 41.265, 28.527, 28.367, 24.174, 23.788, 21.710; HRMS m/z: [M + H] ⁺ C ₂₃ H Calculated for ₂₇ N ₂ O ₃ : 379.2016; Found: 379.2016.

In addition, several different bases, solvents and ligands (eg phosphine ligands) were tested and the results are shown below.

Reaction S-4a: tert-butyl 5-(4-benzamidophenyl)-3,6-dihydropyridine-1(2H)-carboxylate and 5-(4-benzamidophenyl)-3,4-dihydropyridine-1(2H). -Synthesis of tert-butyl carboxylate

In the reactor, THF (639 mL) and tosylate intermediate (tert-butyl 5-(tosyloxy)-3,4-dihydropyridine-1(2H)-carboxylate and 5-(tosyloxy)-3,6-dihydropyridine- Charge 1(2H)-tert-butyl carboxylate) (100 g, 284 mmol, 1.00 eq) and pinacol borane intermediate (96 g, 297 mmol, 1.05 eq). The mixture was stirred and the temperature adjusted to 20°C. A fresh solution of potassium phosphate (192 g) in water (360 mL) was prepared and added dropwise. XPhos (640 mg, 0.005 eq) was added and the reaction mixture was deoxygenated by a vacuum/nitrogen purge cycle. Palladium acetate (250 mg, 0.004 eq) was added, followed by another vacuum/nitrogen purge cycle. The mixture was heated to 65°C and maintained at this temperature for 10 hours. The temperature was adjusted to 25°C and the phases were separated. The organic phase was concentrated under vacuum to approximately 300 mL, then DCM (1011 mL) was added. The resulting mixture was stirred at room temperature for about 2 hours and then filtered through a filter aid (diatomaceous earth). The filtrate was washed twice with water. The organic phase was treated with activated carbon (15 g) at 25° C. for 2 hours and the filter aid diatomaceous earth was added. The mixture was filtered and the filter cake washed with DCM. The solution was concentrated under reduced pressure at about 50°C. 2-Me-THF (550 mL) was added and the mixture was concentrated under reduced pressure to 350 mL at about 50°C. n-Heptane (850 mL) was added at 45°C. The mixture was stirred at 45°C for 2 hours and cooled to 15°C over 4-6 hours. The product was isolated by filtration and the filter cake was washed with a mixture of 2-MeTHF/n-heptane (1:3 v/v, 200 g) then n-heptane (300 g). The wet product was dried under vacuum at 40-60° C. to give 98.8 g (91%) of product. See above data for characterization.

Reaction S-5 (optional): tert-butyl 5-(4-benzamidophenyl)-3,6-dihydropyridine-1(2H)-carboxylate and 5-(4-benzamidophenyl)-3,4-dihydropyridine- Purification of tert-butyl 1(2H)-carboxylate Crude unsaturated aniline derivative (5-(4-benzamidophenyl)-3,6-dihydropyridine-1(2H)-tert-butyl carboxylic acid and 5-(4-benzamide) Phenyl)-3,4-dihydropyridine-1(2H)-carboxylate tert-butyl, 100 g) was charged to the reactor, followed by acetonitrile (CAN, 316 g). The mixture was stirred at 75° C. for 1 hour, then acetonitrile (143 mL) was added. Water (291 g) was added slowly at 75°C. The mixture was stirred at 75°C for 2 hours, then slowly cooled to 4°C over 6 hours and maintained at 4°C for an additional 5 hours. The product was isolated by filtration and the filter cake was washed with acetonitrile:water (2:1, 75g) then water (100g). The wet cake was dried under vacuum at 45° C. for 48 hours to give a purified product (96.0 g, 96%).

Reactions S-6 and S-7: Synthesis of tert-butyl (S)-3-(4-benzamidophenyl)piperidine-1-carboxylate.

In the hydrogenation reactor, unsaturated aniline (5-(4-benzamidophenyl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl and 5-(4-benzamidophenyl)-3,4-dihydropyridine were added. -1 (2H) - tert- carboxylic acid butyl, 100g), Josiphos-SL- J505-2 (770mg), was charged with Rh _(nbd) 2 BF ₄ catalyst (500 mg) and DCM (320 g). The mixture was degassed by successive vacuum/nitrogen backfill cycles. The mixture was saturated with hydrogen gas by continuous vacuum/hydrogen pressurization cycle to 1.55 MPa (224 psi). The temperature of the mixture was heated to 40° C. and the mixture was stirred under a hydrogen pressure of 1.55 MPa (224 psi) for 19 hours. The mixture was cooled to 20° C. and degassed by 5 consecutive vacuum/nitrogen backfill cycles. If the reaction was incomplete, another hydrogenation cycle was performed. When the reaction was complete, DCM (231 g) was added and the mixture was filtered to remove the catalyst. The filter cake was rinsed with DCM (58 g) and the filtrate was concentrated under vacuum at about 55° C. to 210 mL. Ethanol (350 mL) was added and the mixture was concentrated under vacuum at about 55° C. to 420 mL and repeated two more times. Ethanol (115 mL) was added along with hydrous sodium hydroxide (30%, 347 g). The mixture was heated to 80° C. until the reaction was complete. The mixture was cooled to 15° C. and water (996 g) was added. The mixture was stirred at 15° C. for 1.5 hours and the product was isolated by filtration. The filter cake was washed with water and the wet cake was dried under vacuum at 50° C. to give the product (71 g, 96%). ¹ H NMR (400 MHz, CDCl ₃ ), 7.02 (d, J=8 Hz, 2H), 6.62 (d, J=8 Hz, 2H), 4.135 (br s, 2H), 3.601 (s, 2H), 2.69-2.557 (m, 3H), 1.74, (m, 1H), 1.611 (m, 1H), 1.57 (m, 2H), 1.529 (s, 9H).; ¹³ C NMR (CDCl ₃ , 100.61 MHz); 154.892, 144.947, 133.667, 127.893, 115.206, 51.017, 44.243, 43.861, 41.703, 31.947, 28.710, 28.520, 25.6
11; HRMS m/z: [M +H] ⁺ calcd for C ₁₂ H ₁₇ N ₂ O ₂ : 221.1285; Found: 221.1282.

In addition, several additional chiral ligands and solvents were tested and the results are shown below.

Reaction S-8: Synthesis of (S)-4-(1-(tert-butoxycarbonyl)piperidin-3-yl)benzeneaminium ethanesulfonate

The reactor was charged with tert-butyl (S)-3-(4-aminophenyl)piperidine-1-carboxylate (100 g, 362 mmol, 1.0 eq) and acetonitrile (959 g). The temperature was adjusted to 25°C and microcrystalline cellulose (10g) was added. The mixture was stirred for 1.5 hours and filtered. The filter cake was rinsed with acetonitrile (489 g). The filtrate was cooled to 0° C. and methanol (126 g) was added. A solution of ethanesulfonic acid (42.6 g, 1.07 eq) in acetonitrile (87 g) was prepared. A portion of this solution (20%) was added to the reaction mixture at 0°C. A seed of aniline ethanesulfonate (260 mg) was added. The resulting mixture was stirred at about 20° C. for 2 hours, then the rest of the ethanesulfonate solution (106.08 g) was added slowly at 0° C. over 13 hours. The mixture was stirred at 0° C. for 8 hours and the crystalline product was isolated by filtration. The filter cake was washed with a mixture of methanol and acetonitrile (4%) followed by acetonitrile. The wet cake was dried under vacuum at 20° C. for 20 hours to give the product as an off-white solid (108.5 g, 77.6%). ¹ H NMR (400 MHz, CDCl ₃ ); 9.90 (br s, 3H), 7.49 (d, J=8 Hz, 2H), 7.25 (d, J=8 Hz, 2H), 4.12 (br s, 2H) ,1.98 (m, 1H), 1.74 (m, 1H), 1.61-1.56 (m, 2H), 1.45 (s, 9H), 1.106 (t, J=7 Hz, 3H): ¹³ C NMR (DMSO-d ₆ ,100.61 MHz); 154.324, 143.759, 131.021, 128.826, 123.452, 79.172, 45.654, 41.936, 31.670, 28.556, 25.450, 25.363, 10.299; HRMS m/z: [M +H] ⁺ C ₁₂ H ₁₇ N ₂ O Calculated for ₂ : 221.1285; Found: 221.1282.

Furthermore, the preparation of ESA salts from four different solvent systems could be improved to the range of ee to 85-98% ee. The results are shown below.

Example 3-Synthesis of Niraparib Tosylate Monohydrate Example 3 illustrates the synthesis of the compound niraparib tosylate monohydrate (see also Figure 3).

Synthesis of tert-butyl (S)-3-(4-aminophenyl)piperidine-1-carboxylate (aniline free base)

Hydrous sodium hydroxide (1 N, 649 mL, 675 g, 1.2 eq, 3.13 times) was added slowly to a cooled (15° C.) suspension of aniline ESA salt (210 g, 541 mmol) in toluene (2730 g). .. The mixture was stirred for 1 hour and the layers were left to stand. The phases were separated, the organic phase was warmed to 23 °C and washed with water (730 mL, typically 3 times) until the pH of the aqueous phase was between 7-8. A pale yellow solution was obtained (about 2830 g), giving an almost quantitative yield of aniline free base.

Synthesis of methyl 2-azido-3-formylbenzoate (aromatic azide)

A mixture of sodium azide (32.6 g, 1.05 eq) in DMSO (440 g) was stirred at about 25° C. for 20 minutes, then ethyl acetate (450 g) and methyl 3-formyl-2-nitrobenzoate (aldehyde. A, 100 g, 1.0 eq.) was added. The mixture was heated to 40° C. and stirred under a nitrogen purge for about 3 hours. Then ethyl acetate (450 g) and water (500 g) were added to the stirred mixture at 35°C. The phases were separated and the lower phase (aqueous phase) was extracted with ethyl acetate (450 g) at 35°C. The combined organic phases were washed with water at 20° C. to give the product as a solution in ethyl acetate.

Synthesis of (S,E)-3-(4-((2-azido-3-(methoxycarbonyl)benzylidene)amino)phenyl)piperidine-1-carboxylate tert-butyl(imine)

To the solution of aromatic azide in ethyl acetate prepared above was added the aniline free base toluene solution prepared in the previous step (97% by weight of the solution). The mixture was concentrated under vacuum at 45° C. to about 2 L. The mixture was cooled to room temperature and trifluoroacetic acid (55 mg, 0.001 eq) was added. The mixture was stirred at room temperature for about 1 hour and then concentrated under vacuum at about 50° C. to about 1 L. After cooling to room temperature, the solution was used directly in the next step.

Synthesis of (S)-2-(4-(1-(tert-butoxycarbonyl)piperidin-3-yl)phenyl)-2H-indazole-7-carboxylate methyl (heterocyclic ester)

To a stirred suspension of copper(II) triflate (900 mg, 0.005 eq) in THF (1.78 L) at 60°C was added dropwise the imine solution prepared above over 4 hours. After the addition was complete, the mixture was stirred at 60° C. for about 3 hours and then cooled to room temperature. Ethanol (1 L) was added, and the solvent was exchanged with ethanol by concentrating to about 0.8 L under vacuum at 50°C. This was repeated 3 times to obtain an ethanol solution of the heterocyclic ester solution. This solution was used directly in the next step.

Synthesis of (S)-2-(4-(1-(tert-butoxycarbonyl)piperidin-3-yl)phenyl)-2H-indazole-7-carboxylate lithium (lithium salt)

A stirred suspension of lithium hydroxide monohydrate (22.4 g, 1.2 eq) in ethanol (560 mL) was heated to 60 °C. A solution of the heterocyclic ester in ethanol (about 0.8 L, prepared above) was added dropwise over 4 hours while maintaining the temperature at 60°C. The mixture was stirred at 60° C. for about 2 hours until the reaction was complete. The mixture was cooled to about 10° C. and concentrated to 1.2 L by vacuum distillation at about 50° C. The temperature was adjusted to 65° C. and n-heptane (820 mL) was added slowly to the stirred mixture at 65° C. over 8 hours. The mixture was cooled to 23° C. and then stirred at room temperature for about 8 hours. The resulting solid was isolated by filtration and washed with a mixture of ethanol/n-heptane (1:1 V:V) then n-heptane. The wet product was dried under vacuum at about 50° C. to give 176 g of lithium salt (86%). ¹ H NMR (400 MHz, DMSO-d ₆ ); 9.01 (s, 1H), 7.96 (d, J=7.2 Hz, 3H), 7.79 (d, J=8.0, 1 H), 7.34 (d, J= 7.6 Hz, 2 H), 7.15 (dd, J= 8.0, 7.2 Hz, 1 H), 3.97 (br d, J=12, 1 H), 2.78 (br s, 2H), 2.64 (m, 1 H) , 1.85 (m, 1H), 1.68-1.61 (m, 2H), 1.42 (s, 9H); ¹³ C NMR (DMSO-d ₆ ,100.61 MHz); 167.85, 154.35, 148.51, 144.13, 138.48, 130.43, 128.45. , 124.05, 122.77, 122.51, 122.32, 79.19, 41.98, 31.68, 28.59, 25.49; HRMS m/z: [M +H] ⁺ C ₂₄ H ₂₈ N ₃ O ₄ Calculated value: 422.2074; Found value: 422.2068.

Synthesis of 4-methylbenzenesulfonic acid S)-3-(4-(7-carbamoyl-2H-indazol-2-yl)phenyl)piperidin-1-ium monohydrate (niraparib tosylate monohydrate)

To a suspension of lithium salt (100 g, 1.0 eq) in dry DMF (420 mL) was added trifluoroacetic acid (28.4 g, 1.06 eq) slowly at 0-10°C. The mixture was stirred for 30 minutes and carbonyldiimidazole (CDI, 52.8g, 1.39eq) was added portionwise at 0-10<0>C. The mixture was warmed to about 17-27°C and allowed to stir for about 3-4 hours. After the reaction was completed, the batch was cooled to 5-10°C and ammonium hydroxide aqueous solution (27.2g, about 29wt%, and 2.0eq) was gradually added while maintaining the internal temperature between 5-20°C. added. The mixture was warmed to 15-23°C and stirred for about 30 minutes. Water (995 g) was added, followed by ethyl acetate (1332 g). The mixture was stirred at 15-25°C for at least 30 minutes and left to stand. The layers were separated and the organic phase was washed with aqueous ammonium hydroxide (140 mL, about 6%) as needed to remove any residual Boc heterocyclic acid from the ethyl acetate solution. The organic layer was washed with 5% brine (3 x 340 mL). The organic phase was concentrated by vacuum distillation to about 640 mL. THF (845 g) was added and vacuum distillation to 640 mL was repeated. The temperature of the solution was cooled to 15-25 ° C., para - toluenesulfonic acid monohydrate _{(pTsOH.H 2 O) (99.5g,} 2.23 eq) was added. The mixture was stirred at room temperature for about 30 minutes and refluxed for about 14 hours. Upon completion of the de-Boc reaction, the mixture was cooled to 17-27°C and water (89g) was added. The mixture was stirred at about 17-27°C for 3-4 hours and the crude product was isolated by filtration. The filter cake was washed with THF and dried under vacuum below 35° C. to give crude niraparib tosylate monohydrate (108 g, 91%).

Optical enrichment

To a mixture of acetonitrile (1580 g) and water (2000 g) was added crude niraparib tosylate monohydrate (100 g active enantiomer). The mixture was stirred at 18-26°C for about 3 hours. The mixture was filtered through a cartridge containing activated carbon. The filtrate was concentrated by vacuum distillation at about 45° C. to 1.340 mL. The mixture was cooled to 15-25°C and held for 1 hour. The product was isolated by filtration and the filter cake washed with water. The product was dried under vacuum at about 45° C. for hours to yield 90 g (87%) of optically enriched nilaparib tosylate monohydrate.

Physical form/particle size adjustment

Water (8.0 L) was charged to the reactor and the temperature was adjusted to 20-30°C. Optically enriched nilaparib tosylate monohydrate (1.00 kg) was charged to the second reactor followed by DMSO (4.39 kg). The mixture was stirred, heated to 28-38°C and stirred until all solids had dissolved. This solution was then filtered into the water in the first reactor while maintaining the temperature of the crystallization reactor at 20-30°C. The mixture was stirred for 1-2 hours. Optionally, the resulting mixture may be transferred to another reactor via a wet mill if necessary to reduce particle size. The mixture was stirred, heated and then gradually cooled. This temperature cycling (annealing) can be repeated if desired. The final product was isolated by filtration and the filter cake washed with water. The wet cake was dried under vacuum at about 45° C. to yield 0.9 kg (90%) nilaparib tosylate monohydrate. ¹ H NMR (400 MHz, CD ₃ OD) 8.97 (s, 1H), 8.15 (dd, J=0.9,7.1, 2H), 8.04 (d, J=8.6, 2H), 8.01 (dd, J=0.9, 8.4, 2H), 7.72 (d, J = 8.1, 2H), 7.51 (d, J =7.9,2H), 7.27 (dd, J=7.1, 8.4, 2H), 7.22 (d, J=7.7, 4H) , 3.49-3.44 (om, 2H), 3.19-3.06 (om, 2H), 3.11 (om, 2H), 2.34 (s, 3H), 2.10-2.09 (om, 2H), 1.94-1.87 (om, 2H) ¹³ C NMR (100.6 MHz, CD ₃ OD), 169.6, 148.0, 143.6, 143.0, 141.8, 140.4, 131.7, 129.9, 129.7, 127.2, 127.0, 125.3, 124.1, 123.1, 122.3, 121.9, 50.1, 45.1, 41.0 , 30.8, 23.9, 21.3; HRMS observation m/z = 321.1717 (calculation m/z 321.1710).

While the preferred embodiments of the invention have been illustrated and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Many variations, modifications, and substitutions will occur to those skilled in the art without departing from the invention. It should be noted that in practicing the present invention, various alternatives to the embodiments of the invention described herein may be used. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims (194)

A method for producing a compound of formula (1) or a salt thereof, comprising:
A method comprising contacting a compound of formula (2) or salt thereof with a compound of formula (3) or salt thereof:
[In the formula,
R ₁ is H or an amine protecting group;
R ₂ is H, C _1-10 alkyl, C _1-10 haloalkyl, or aryl; and each R ₃ is independently H, halogen, C _1-10 alkyl, C _1-10 haloalkyl, or aryl. Is]. The method of claim 1, wherein the contacting results in the formation of water molecules. The method according to claim 1 or 2, wherein the contacting is performed in the presence of an acid. The acid is formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, oxalic acid, lactic acid, malic acid, citric acid, benzoic acid, carbonic acid, uric acid, taurine, p-toluenesulfonic acid, trifluoromethanesulfonic acid, 4. The method of claim 3, which is aminomethylphosphonic acid, trifluoroacetic acid (TFA), phosphonic acid, sulfuric acid, nitric acid, phosphoric acid, hydrochloric acid, ethanesulfonic acid (ESA), or any combination thereof. The method of claim 4, wherein the acid is TFA. R ₁ is an amine protecting group, the process according to any one of claims 1 to 5. The amine protecting group is tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), carboxybenzyl group (Cbz), p-methoxybenzylcarbonyl (Moz), acetyl (Ac), benzoyl( Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2-naphthylmethyl ether (Nap), tosyl (Ts), or trichloroethyl chloroformate (Troc). ) Is the method of claim 6. The method according to claim 7, wherein the amine protecting group is a tert-butyloxycarbonyl group (Boc). R ₂ is _{C 1-10} alkyl A process according to any one of claims 1-8. R ₂ is methyl, A method according to claim 9. Each _{R 3} is H, A method according to any one of claims 1 to 10. The compound of the formula (1) or a salt thereof has the formula (4):
The method of claim 11, having the structure: The compound of the formula (1) or a salt thereof has the formula (4):
The method of claim 1, having the structure: A method for producing a compound of formula (5) or a salt thereof, comprising:
A method comprising contacting a compound of formula (1) or salt thereof with a catalyst:
[In the formula,
R ₁ is H or an amine protecting group;
R ₂ is H, C _1-10 alkyl, C _1-10 haloalkyl, or aryl; and each R ₃ is independently H, halogen, C _1-10 alkyl, C _1-10 haloalkyl, or aryl. Is]. 15. The method of claim 14, wherein the catalyst comprises a Lewis acid, or solvate thereof. The Lewis acid has the formula MXn, where M is Cu, Zn, B, Ti, Fe, Ni, Co, Al, or Ag, where X is a halide, triflate, phosphoric acid. 16. The method of claim 15, which is a salt, a fluorophosphate, or an acetate, where n is 1, 2, 3, or 4. 17. The method of claim 16, wherein M is Cu. 17. The method of claim 16, wherein the Lewis acid is a copper salt. 19. The method of claim 18, wherein the copper salt is copper(II) trifluoromethanesulfonate (Cu(OTf) ₂ ). The method according to any one of claims 14 to 19, wherein the contacting is performed in the presence of a solvent. The solvent is N,N-dimethylformide (DMF), t-butanol, dimethoxyethane (DME), acetonitrile, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran (ME-THF), isopropyl. 21. The method of claim 20, comprising alcohol, methanol, ethanol, or any combination thereof. 22. The method of claim 21, wherein the solvent comprises THF. R ₁ is an amine protecting group, the process according to any one of claims 14 to 22. The amine protecting group is tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), carboxybenzyl group (Cbz), p-methoxybenzylcarbonyl (Moz), acetyl (Ac), benzoyl( Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2-naphthylmethyl ether (Nap), tosyl (Ts), or trichloroethyl chloroformate (Troc). ) Is a method according to claim 23. 25. The method of claim 24, wherein the amine protecting group is a tert-butyloxycarbonyl group (Boc). R ₂ is _{C 1-10} alkyl, The method according to any one of claims 14 to 25. R ₂ is methyl, A method according to claim 26. Each _{R 3} is H, A method according to any one of claims 14 to 27. The compound of the formula (5) or a salt thereof has the formula (6):
29. The method of claim 28, having the structure: The compound of the formula (5) has the formula (6):
15. The method of claim 14, having the structure: A method for producing a salt of formula (7), comprising:
A method comprising contacting a compound of formula (5) or salt thereof with a metal hydroxide:
[In the formula,
R ₁ is H or an amine protecting group;
R ₂ is H, C _1-10 alkyl, C _1-10 haloalkyl, or aryl;
Each R ₃ is independently H, halogen, C _1-10 alkyl, C _1-10 haloalkyl, or aryl; and A is a cation]. 32. The method of claim 31, wherein the cation is an alkali metal cation. 33. The method of claim 32, wherein the alkali metal cation is a lithium cation. R ₁ is an amine protecting group, the process according to any one of claims 31 to 33. The amine protecting group is tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), carboxybenzyl group (Cbz), p-methoxybenzylcarbonyl (Moz), acetyl (Ac), benzoyl( Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2-naphthylmethyl ether (Nap), tosyl (Ts), or trichloroethyl chloroformate (Troc). 35.) The method of claim 34. 36. The method of claim 35, wherein the amine protecting group is a tert-butyloxycarbonyl group (Boc). R ₂ is _{C 1-10} alkyl, The method according to any one of claims 31 to 36. R ₂ is methyl, A method according to claim 37. Each _{R 3} is H, A method according to any one of claims 31 to 38. The salt of the formula (7) is represented by the formula (8):
40. The method of claim 39 having the structure: A method for producing a compound of formula (9) or a salt thereof, comprising:
A method comprising contacting a compound of formula (7) or salt thereof with a coupling reagent and ammonium hydroxide:
[In the formula,
R ₁ is H or an amine protecting group;
R ₂ is H, C _1-10 alkyl, C _1-10 haloalkyl, or aryl;
Each R ₃ is independently H, halogen, C _1-10 alkyl, C _1-10 haloalkyl, or aryl; and A is a cation]. 42. The method of claim 41, wherein the cation is an alkali metal cation. 43. The method of claim 42, wherein the alkali metal cation is a lithium cation. 44. The method of any of claims 41-43, wherein the contacting is performed in the presence of a solvent. The solvent is N,N-dimethylformide (DMF), t-butanol, dimethoxyethane (DME), acetonitrile, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran (ME-THF), isopropyl. 45. The method of claim 44, comprising alcohol, methanol, ethanol, or any combination thereof. 46. The method of claim 45, wherein the solvent comprises DMF. 47. The method of claims 41-46, wherein the contacting is performed in the presence of acid. The acid is formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, oxalic acid, lactic acid, malic acid, citric acid, benzoic acid, carbonic acid, uric acid, taurine, p-toluenesulfonic acid, trifluoromethanesulfonic acid, 48. The method of claim 47, which is aminomethylphosphonic acid, trifluoroacetic acid (TFA), phosphonic acid, sulfuric acid, nitric acid, phosphoric acid, hydrochloric acid, ethanesulfonic acid (ESA), or any combination thereof. 49. The method of claim 48, wherein the acid is trifluoroacetic acid (TFA). The coupling reagent is carbonyldiimidazole (CDI), N,N′-dicyclohexylcarbodiimide (DCC), 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT). ), N,N′-diisopropylcarbodiimide, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 2 -(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 1-hydroxy-7-azabenzotriazole (HOAt), hydroxybenzotriazole (HOBt) ), 7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP). 50. The method according to any one of to 49. 51. The method of claim 50, wherein the coupling reagent is CDI. R ₁ is an amine protecting group, the process according to any one of claims 41 to 51. The amine protecting group is tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), carboxybenzyl group (Cbz), p-methoxybenzylcarbonyl (Moz), acetyl (Ac), benzoyl( Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2-naphthylmethyl ether (Nap), tosyl (Ts), or trichloroethyl chloroformate (Troc). ) Is the method of claim 52. 54. The method of claim 53, wherein the amine protecting group is a tert-butyloxycarbonyl group (Boc). R ₂ is _{C 1-10} alkyl, The method according to any one of claims 41-54. R ₂ is methyl, A method according to claim 55. Each _{R 3} is H, A method according to any one of claims 41 to 56. The compound of the formula (9) or a salt thereof has the formula (10):
58. The method of claim 57 having the structure: The compound of formula (9) has the formula (10):
42. The method of claim 41, having the structure: A method for producing a salt of formula (11), comprising:
Compounds of formula (9) or a salt thereof para - comprising contacting toluenesulfonic acid monohydrate (pTSA · H 2 _O), method:
[In the formula,
R ₁ is H or an amine protecting group;
R ₂ is H, C _1-10 alkyl, C _1-10 haloalkyl, or aryl; and each R ₃ is independently H, halogen, C _1-10 alkyl, C _1-10 haloalkyl, or aryl. Is]. 61. The method of claim 60, wherein the contacting is in the presence of acid. The acid is formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, oxalic acid, lactic acid, malic acid, citric acid, benzoic acid, carbonic acid, uric acid, taurine, p-toluenesulfonic acid, trifluoromethanesulfonic acid, 62. The method of claim 61, which is aminomethylphosphonic acid, trifluoroacetic acid (TFA), phosphonic acid, sulfuric acid, nitric acid, phosphoric acid, hydrochloric acid, ethanesulfonic acid (ESA), or any combination thereof. 63. The method of claim 62, wherein the acid is trifluoroacetic acid (TFA). 64. The method of any of claims 60-63, wherein the contacting is performed in the presence of a solvent. The solvent is N,N-dimethylformide (DMF), t-butanol, dimethoxyethane (DME), acetonitrile, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran (ME-THF), isopropyl. 66. The method of claim 64, comprising alcohol, methanol, ethanol, or any combination thereof. 66. The method of claim 65, wherein the solvent comprises THF. R ₁ is an amine protecting group, the process according to any one of claims 60 to 66. The amine protecting group is tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), carboxybenzyl group (Cbz), p-methoxybenzylcarbonyl (Moz), acetyl (Ac), benzoyl ( Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2-naphthylmethyl ether (Nap), tosyl (Ts), or trichloroethyl chloroformate (Troc). 68. The method of claim 67, wherein 69. The method of claim 68, wherein the amine protecting group is a tert-butyloxycarbonyl group (Boc). R ₂ is _{C 1-10} alkyl, The method according to any one of claims 60 to 69. R ₂ is methyl, A method according to claim 70. Each _{R 3} is H, A method according to any one of claims 60 to 71. The salt of the formula (11) has the formula (12):
73. The method of claim 72 having the structure of: A method for producing an enantiomerically enriched tosylic acid (S)-nilaparib monohydrate of formula (12), comprising:
a) contacting a mixture comprising (R)-niraparib monohydrate tosylate and (S)-niraparib monohydrate tosylate with water and a first organic solvent;
b) separating the tosylate (S)-nilaparib monohydrate from the mixture by filtration to form the enantiomerically enriched tosylate (S)-nilaparib monohydrate; and c) the enantiomerically enriched tosyl. Acid (S)-nilaparib monohydrate is contacted with a second organic solvent, water, or any combination thereof to form a crystalline form of the enantiomerically enriched tosylate (S)-nilaparib monohydrate. Letting,
A method comprising:. 77. The method of claim 74, further comprising wet milling the crystalline form of the enantiomerically enriched (S)-nilaparib monohydrate tosylate. 76. The method of claim 74 or 75, further comprising annealing the enantiomerically enriched (S)-nilaparib monohydrate with one or more temperature cycles. 77. The method of any one of claims 74-76, wherein the first organic solvent comprises acetonitrile. 78. The method of any one of claims 74-77, wherein a water:first organic solvent ratio (v/v) of about 200:1 to about 1:200 is used for said contacting. 79. The method of claim 78, wherein the water:first organic solvent ratio (v/v) is about 5:1 to about 1:5. 80. The method of any one of claims 74-79, wherein the enantiomerically enriched tosylate (S)-nilaparib monohydrate is present in the filtrate portion after the filtration. 81. The method of any of claims 74-80, wherein the second organic solvent comprises DMSO. 82. The method of claim 81, comprising contacting the enantiomerically enriched tosylic acid (S)-nilaparib monohydrate with dimethyl sulfoxide (DMSO) and water. 83. The method of claim 81 or 82, wherein a water:DMSO ratio (v/v) of about 200:1 to about 1:200 is used for said contacting. 84. The method of claim 83, wherein the water:DMSO ratio (v/v) is about 5:1 to about 1:5. A method for producing an enantiomerically enriched tosylic acid (S)-nilaparib monohydrate of formula (12), comprising:
a) contacting a salt of formula (13) with sodium hydroxide and toluene to form a compound of formula (14);
b) contacting a compound of formula (15) with sodium azide, ethyl acetate and DMSO to form a compound of formula (16);
c) contacting a compound of formula (14) with a compound of formula (16) and TFA to form a compound of formula (4);
d) contacting a compound of formula (4) with copper(II) trifluoromethanesulfonate (Cu(OTf) ₂ ), THF and toluene to form a compound of formula (6);
e) contacting a compound of formula (6) with lithium hydroxide and ethanol to form a salt of formula (8);
f) contacting the salt of formula (8) with CDI, TFA, N,N-dimethylformide (DMF), and ammonium hydroxide to form a compound of formula (10);
g) contacting the compound of formula (10) with p-toluenesulfonic acid monohydrate (pTsOH.H ₂ O) and THF to form the tosylate (S)-nilaparib monohydrate of formula (12). To make;
h) contacting (S)-nilaparib monohydrate of formula (12) with acetonitrile and water to form a mixture;
i) separating the tosylate (S)-nilaparib monohydrate from the mixture by filtration to form the enantiomerically enriched tosylate (S)-nilaparib monohydrate; and j) the enantiomerically enriched tosyl. Contacting the acid (S)-nilaparib monohydrate with DMSO and water to form a crystalline form of the enantiomerically enriched (S)-nilaparib monohydrate.
A method comprising:. 86. The method of claim 85, further comprising wet milling the crystalline form of the enantiomerically enriched (S)-nilaparib monohydrate tosylate. 86. The method of claim 85, further comprising annealing the enantiomerically enriched (S)-nilaparib monohydrate with one or more temperature cycles. Salt of formula (7):
[In the formula,
R ₁ is H or an amine protecting group;
Each R ₃ is independently H, halogen, C _1-10 alkyl, C _1-10 haloalkyl, or aryl; and A is a cation]. 89. The salt of claim 88, wherein the cation is an alkali metal cation. 90. The salt of claim 89, wherein the alkali metal cation is a lithium cation. R ₁ is an amine protecting group, salt of any one of claims 88-90. The amine protecting group is tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), carboxybenzyl group (Cbz), p-methoxybenzylcarbonyl (Moz), acetyl (Ac), benzoyl( Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2-naphthylmethyl ether (Nap), tosyl (Ts), or trichloroethyl chloroformate (Troc). 94.) The salt of claim 91 which is 93. The salt of claim 92, wherein the amine protecting group is a tert-butyloxycarbonyl group (Boc). Each _{R 3} is H, salts of any one of claims 88-93. The salt of the formula (7) is represented by the formula (8):
95. The salt of claim 94 having the structure: A method for producing a compound of formula (17) or a salt thereof, comprising:
A method comprising contacting a compound of formula (18) or salt thereof with n-butyllithium and triisopropyl borate (B(Oi-Pr) ₃ ):
[In the formula, R ₄ is a leaving group]. 97. The method of claim 96, comprising contacting a compound of formula (19) or salt thereof with benzoyl chloride and an organic compound to form a compound of formula (18) or salt thereof:
[In the formula, R ₄ is a leaving group]. 98. The method of claim 97, wherein the organic compound is triethylamine (TEA) or trimethylamine (TMA). R ₄ is Br, A method according to any one of claims 96 to 98. 100. The method of any of claims 96-99, wherein the contacting is performed in the presence of a solvent. The solvent is N,N-dimethylformide (DMF), t-butanol, dimethoxyethane (DME), acetonitrile, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran (ME-THF), isopropyl. 101. The method of claim 100, comprising alcohol, methanol, ethanol, or any combination thereof. 102. The method of claim 101, wherein the solvent comprises THF. A method for producing a compound of formula (20) or a salt thereof, comprising:
A method comprising contacting a compound of formula (17) or salt thereof with a salt of formula (21) in the presence of a catalyst.
The contact of the compound of the formula (17) or a salt thereof with the compound of the formula (22):
104. The method of claim 103, further comprising contacting the salt of. 105. The method of claim 104, wherein the salt of formula (21) and the salt of formula (22) have a ratio (w/w) of about 50:1 to about 1:50. 106. The method of claim 105, wherein the ratio (w/w) is about 7:1. 107. The method of any of claims 103-106, wherein the contacting is in the presence of a ligand. 108. The method of claim 107, wherein the ligand comprises a phosphine ligand. 109. The method of claim 108, wherein the phosphine ligand comprises DavePhos, XantPhos, JohnPhos, SPhos, XPhos, tBuXPhos, APhos, CyJohnPhos, or any combination thereof. 110. The method of claim 109, wherein the phosphine ligand comprises XPhos. 111. The method of any of claims 103-110, wherein the catalyst comprises a metal catalyst. 112. The method of claim 111, wherein the metal catalyst comprises palladium. 113. The method of claim 112, wherein the metal catalyst comprises palladium (II) acetate. 114. The method of any of claims 103-113, wherein the contacting is performed in the presence of a base. 115. The method of claim 114, wherein the base comprises an alkali salt. The alkali _salt, include _{Cs 2 CO 3, CsHCO 3 K} 3 PO 4, K 2 HPO 4, KH 2 PO 4, K 2 CO 3, KHCO 3, NaHCO 3, Na 2 CO 3 , or any combination thereof, 116. The method of claim 115, consisting of 117. The method of any of claims 103-116, wherein the contacting is in the presence of a solvent. The solvent is N,N-dimethylformide (DMF), t-butanol, dimethoxyethane (DME), acetonitrile, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran (ME-THF), isopropyl. 118. The method of claim 117, comprising alcohol, methanol, ethanol, or any combination thereof. 118. The method of claim 118, wherein the solvent comprises THF. 120. The method of any one of claims 103-119, further comprising contacting the compound of formula (20) or salt thereof with acetonitrile. A method for producing a compound of formula (23) or a salt thereof, comprising:
A compound of formula (17) or a salt thereof
A method comprising contacting with:
[Wherein each R ₅ is independently H or C _1-3 alkyl]. Each _{R 5} is _{C 1-3} alkyl independently method of claim 121. Each _{R 5} is methyl The method of claim 122. The compound of the formula (23) or a salt thereof has the formula (24):
124. The method of claim 123, having the structure of: 125. The method according to any one of claims 121-124, wherein the contacting is performed in the presence of a solvent. The solvent is N,N-dimethylformide (DMF), t-butanol, dimethoxyethane (DME), acetonitrile, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran (ME-THF), isopropyl. 126. The method of claim 125, comprising alcohol, methanol, ethanol, or any combination thereof. 127. The method of claim 126, wherein the solvent comprises THF. A method for producing a compound of formula (20) or a salt thereof, comprising:
The compound of the formula (23) or a salt thereof is converted into the formula (21):
Contacting the salt of claim 1 in the presence of a catalyst.
The contact of the compound of the formula (23) or a salt thereof with the compound of the formula (22):
129. The method of claim 128, further comprising contacting the salt of. 130. The method of claim 129, wherein the salt of formula (21) and the salt of formula (22) have a ratio (w/w) of about 50:1 to about 1:50. 131. The method of claim 130, wherein the ratio (w/w) is about 7:1. 132. The method of any one of claims 128-131, wherein the contacting is in the presence of a ligand. 133. The method of claim 132, wherein the ligand comprises a phosphine ligand. 138. The method of claim 133, wherein the phosphine ligand comprises DavePhos, XantPhos, JohnPhos, SPhos, XPhos, tBuXPhos, APhos, CyJohnPhos, or any combination thereof. 136. The method of claim 134, wherein the phosphine ligand comprises XPhos. 136. The method of any one of claims 128-135, wherein the catalyst comprises a metal catalyst. 138. The method of claim 136, wherein the metal catalyst comprises palladium. 138. The method of claim 137, wherein the metal catalyst comprises palladium (II) acetate. 139. The method of any one of claims 128-138, wherein the contacting is performed in the presence of a base. 140. The method of claim 139, wherein the base comprises an alkali salt. The alkali _salt, include _{Cs 2 CO 3, CsHCO 3 K} 3 PO 4, K 2 HPO 4, KH 2 PO 4, K 2 CO 3, KHCO 3, NaHCO 3, Na 2 CO 3 , or any combination thereof, 141. The method of claim 140, consisting of 146. The method of any one of claims 128-141, wherein the contacting is performed in the presence of a solvent. The solvent is N,N-dimethylformide (DMF), t-butanol, dimethoxyethane (DME), acetonitrile, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran (ME-THF), isopropyl. 143. The method of claim 142, comprising alcohol, methanol, ethanol, or any combination thereof. 144. The method of claim 143, wherein the solvent comprises THF. 158. The method of any one of claims 128-144, further comprising contacting the compound of formula (20) or salt thereof with acetonitrile. A method for producing a compound of formula (25) or a salt thereof, comprising:
A method comprising contacting a compound of formula (20) or salt thereof with a ligand.
146. The method of claim 146, further comprising contacting a compound of formula (26) or salt thereof with the ligand.
148. The method of claim 147, wherein the ligand comprises a chiral ligand. 149. The method of claim 148, wherein the chiral ligand comprises a Josiphos ligand. 149. The method of claim 149, wherein the Josiphos ligand comprises Josiphos SL-J505-2, Josiphos SL-J013, Josiphos SL-J212, Josiphos SL-J011, Josiphos SL-N012, or any combination thereof. Method. 151. The method of any one of claims 146-150, wherein the contacting is performed in the presence of a metal salt. The metal salt, comprising a tetrafluoroborate bis (Noruboruenajin) rhodium _{(I) (Rh (nbd)} 2 BF 4), The method of claim 151. 153. The method of any one of claims 146-152, wherein the contacting is performed in the presence of a solvent. The solvent is N,N-dimethylformide (DMF), t-butanol, dimethoxyethane (DME), acetonitrile, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran (ME-THF), isopropyl. 154. The method of claim 153, comprising alcohol, methanol, ethanol, or any combination thereof. 155. The method of claim 154, wherein the solvent comprises DCM. A method for producing a compound of formula (14) or a salt thereof, comprising:
A method comprising contacting a compound of formula (25) or salt thereof with a base.
157. The method of claim 156, wherein the base comprises alkali hydroxide. 160. The method of claim 157, wherein the alkali hydroxide comprises sodium hydroxide. 159. The method of any one of claims 156-158, wherein the contacting is performed in the presence of a solvent. The solvent is N,N-dimethylformide (DMF), t-butanol, dimethoxyethane (DME), acetonitrile, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran (ME-THF), isopropyl. 160. The method of claim 159, comprising alcohol, methanol, ethanol, or any combination thereof. 166. The method of claim 160, wherein the solvent comprises ethanol. A method for producing a salt of formula (13), comprising:
A method comprising contacting a compound of formula (14) or salt thereof with an acid.
The acid is formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, oxalic acid, lactic acid, malic acid, citric acid, benzoic acid, carbonic acid, uric acid, taurine, p-toluenesulfonic acid, trifluoromethanesulfonic acid, 163. The method of claim 162, which is aminomethylphosphonic acid, trifluoroacetic acid (TFA), phosphonic acid, sulfuric acid, nitric acid, phosphoric acid, hydrochloric acid, ethanesulfonic acid (ESA), or any combination thereof. 165. The method of claim 163, wherein the acid is ESA. 166. The method of any one of claims 162-164, wherein the contacting is in the presence of a solvent. The solvent is N,N-dimethylformide (DMF), t-butanol, dimethoxyethane (DME), acetonitrile, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran (ME-THF), isopropyl. 166. The method of claim 165, comprising alcohol, methanol, ethanol, or any combination thereof. 166. The method of claim 166, wherein the solvent comprises acetonitrile, methanol, DCM, or any combination thereof. 166. The method of claim 167, wherein the solvent comprises acetonitrile and methanol. 169. The method of claim 168, wherein the solvent has a methanol:acetonitrile ratio of 1% to 50% (v/v). 166. The method of claim 167, wherein the solvent comprises acetonitrile and DCM. 170. The method of claim 170, wherein the solvent has a DCM:acetonitrile ratio of 1% to 50% (v/v). Formula (21):
A method for producing the compound or a salt thereof, comprising:
a) Formula (28):
Of the compound of formula (29):
Forming a compound of formula (29) or a salt thereof; and b) contacting the compound of formula (29) or salt thereof with p-toluenesulfonic anhydride.
A method comprising:. 175. The method of claim 172, wherein the oxidant is 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO). 174. The method of claim 173, wherein the oxidizing or contacting is performed in the presence of a solvent. The solvent is N,N-dimethylformide (DMF), t-butanol, dimethoxyethane (DME), acetonitrile, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyltetrahydrofuran (ME-THF), isopropyl. 175. The method of claim 174, comprising alcohol, methanol, ethanol, or any combination thereof. 176. The method of claim 175, wherein the solvent comprises DCM. Formula (28):
177. The method of any one of claims 172-176, wherein the oxidation of the compound of claim 1 or a salt thereof is performed in the presence of sodium bicarbonate, potassium bromide, sodium sulfite, or any combination thereof. 178. Any of claims 172-177, wherein contacting the compound of formula (29) or salt thereof is carried out in the presence of trimethylamine (TEA), water, isopropyl alcohol, sodium azide, or any combination thereof. The method described in paragraph 1. The compound of formula (29) or a salt thereof is contacted with the compound of formula (21):
And a compound of the above formula (22):
179. The method of any one of claims 172-178, which results in the formation of a mixture of compounds of claim. A composition of formula (30) or salt thereof:
[In the formula,
Each R ₁ is independently H or an amine protecting group; and each R ₃ is independently H, halogen, C _1-10 alkyl, C _1-10 haloalkyl, or aryl]. The composition of claim 180, or a salt thereof, wherein each R ₁ is independently an amine protecting group. The amine protecting group is tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), carboxybenzyl group (Cbz), p-methoxybenzylcarbonyl (Moz), acetyl (Ac), benzoyl( Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2-naphthylmethyl ether (Nap), tosyl (Ts), or trichloroethyl chloroformate (Troc). 184) The composition of claim 181, or a salt thereof. 183. The composition or salt thereof according to claim 182, wherein the amine protecting group is a tert-butyloxycarbonyl group (Boc) or benzoyl (Bz). Each _{R 3} is H, A composition according to any one of claims 180-183. The compound or salt thereof has the formula (25):
184. The composition of claim 184, having the structure of: The compound has the formula (25):
181. The composition of claim 180, having the structure of: A composition of formula (31) or (32) or salt thereof:
[In the formula,
Each R ₁ is independently H or an amine protecting group; and each R ₃ is independently H, halogen, C _1-10 alkyl, C _1-10 haloalkyl, or aryl]. 187. The composition of claim 187 or salt thereof, wherein each R< ₁ > is independently an amine protecting group. The amine protecting group is tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), carboxybenzyl group (Cbz), p-methoxybenzylcarbonyl (Moz), acetyl (Ac), benzoyl ( Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2-naphthylmethyl ether (Nap), tosyl (Ts), or trichloroethyl chloroformate (Troc). ) The composition of claim 188 or a salt thereof. 189. The composition or a salt thereof according to claim 189, wherein the amine protecting group is a tert-butyloxycarbonyl group (Boc) or benzoyl (Bz). Each _{R 3} is H, A composition according to any one of claims 187-190. The compound or salt thereof has the formula (20) or (26):
192. The composition of claim 191, having the structure of: The compound has the formula (20):
188. The composition of claim 187, having the structure of: The compound has formula (26):
188. The composition of claim 187, having the structure of: